Skip to main content

Advertisement

Springer Nature Link
Log in

YB-1 activating cascades as potential targets in KRAS-mutated tumors

  • Review Article
  • Published:
Strahlentherapie und Onkologie Aims and scope Submit manuscript

Abstract

Y‑box binding protein‑1 (YB-1) is a multifunctional protein that is highly expressed in human solid tumors of various entities. Several cellular processes, e.g. cell cycle progression, cancer stemness and DNA damage signaling that are involved in the response to chemoradiotherapy (CRT) are tightly governed by YB‑1. KRAS gene with about 30% mutations in all cancers, is considered the most commonly mutated oncogene in human cancers. Accumulating evidence indicates that oncogenic KRAS mediates CRT resistance. AKT and p90 ribosomal S6 kinase are downstream of KRAS and are the major kinases that stimulate YB‑1 phosphorylation. Thus, there is a close link between the KRAS mutation status and YB‑1 activity. In this review paper, we highlight the importance of the KRAS/YB‑1 cascade in the response of KRAS-mutated solid tumors to CRT. Likewise, the opportunities to interfere with this pathway to improve CRT outcome are discussed in light of the current literature.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dolfini D, Mantovani R (2013) Targeting the Y/CCAAT box in cancer: YB‑1 (YBX1) or NF-Y? Cell Death Differ 20(5):676–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lindquist JA, Mertens PR (2018) Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal 16(1):63

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhan Y et al (2022) YB1 associates with oncogenetic roles and poor prognosis in nasopharyngeal carcinoma. Sci Rep 12(1):3699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yahata H et al (2002) Increased nuclear localization of transcription factor YB‑1 in acquired cisplatin-resistant ovarian cancer. J Cancer Res Clin Oncol 128(11):621–626

    Article  CAS  PubMed  Google Scholar 

  5. Nishio S et al (2014) Nuclear Y‑box-binding protein‑1 is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer. Gynecol Oncol 132(3):703–708

    Article  CAS  PubMed  Google Scholar 

  6. Dahl E et al (2009) Nuclear detection of Y‑boxprotein‑1 (YB-1) closely associates with progesterone receptor negativity and is a strong adverse survival factor in human breast cancer. BMC Cancer 9(1):410

    Article  PubMed  PubMed Central  Google Scholar 

  7. Fushimi F et al (2013) Peroxiredoxins, thioredoxin, and Y‑box-binding protein‑1 are involved in the pathogenesis and progression of dialysis-associated renal cell carcinoma. Virchows Arch 463(4):553–562

    Article  CAS  PubMed  Google Scholar 

  8. Sheridan CM et al (2015) YB‑1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence. Oncotarget 6(10):7470–7480

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shibahara K et al (2001) Nuclear expression of the Y‑box binding protein, YB‑1, as a novel marker of disease progression in non-small cell lung cancer1. Clin Cancer Res 7(10):3151–3155

    CAS  PubMed  Google Scholar 

  10. Guo T et al (2017) YB‑1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma. Oncotarget 8(29):48110–48125

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sinnberg T et al (2012) MAPK and PI3K/AKT mediated YB‑1 activation promotes melanoma cell proliferation which is counteracted by an autoregulatory loop. Exp Dermatol 21(4):265–270

    Article  CAS  PubMed  Google Scholar 

  12. Song YH et al (2014) Twist1 and Y‑box-binding protein‑1 are potential prognostic factors in bladder cancer. Urol Oncol 32(1):31.e1–31.e7

    Article  CAS  PubMed  Google Scholar 

  13. Chao H‑M et al (2016) Y‑box binding protein‑1 promotes hepatocellular carcinoma-initiating cell progression and tumorigenesis via Wnt/β-catenin pathway. Oncotarget 8(2):2604–2616

    Article  PubMed Central  Google Scholar 

  14. Yan X et al (2014) High expression of Y‑box-binding protein 1 is associated with local recurrence and predicts poor outcome in patients with colorectal cancer. Int J Clin Exp Pathol 7(12):8715–8723

    PubMed  PubMed Central  Google Scholar 

  15. Zhang Y et al (2012) Overexpression of Y‑box binding protein‑1 in cervical cancer and its association with the pathological response rate to chemoradiotherapy. Med Oncol 29(3):1992–1997

    Article  CAS  PubMed  Google Scholar 

  16. Mylona E et al (2014) Y‑box-binding protein 1 (YB1) in breast carcinomas: relation to aggressive tumor phenotype and identification of patients at high risk for relapse. Eur J Surg Oncol 40(3):289–296

    Article  CAS  PubMed  Google Scholar 

  17. Shibahara K et al (2004) Targeted disruption of one allele of the Y‑box binding protein‑1 (YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin and mitomycin C. Cancer Sci 95(4):348–353

    Article  CAS  PubMed  Google Scholar 

  18. Chatterjee M et al (2008) The Y‑box binding protein YB‑1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma. Blood 111(7):3714–3722

    Article  CAS  PubMed  Google Scholar 

  19. Kim ER et al (2013) The proteolytic YB‑1 fragment interacts with DNA repair machinery and enhances survival during DNA damaging stress. Cell Cycle 12(24):3791–3803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Johnson TG et al (2019) Why be one protein when you can affect many? The multiple roles of YB‑1 in lung cancer and mesothelioma. Front Cell Dev Biol 7:221

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kohno Y et al (2006) Expression of Y‑box-binding protein dbpC/contrin, a potentially new cancer/testis antigen. Br J Cancer 94(5):710–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lyabin DN et al (2020) YB‑3 substitutes YB‑1 in global mRNA binding. RNA Biol 17(4):487–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang GR et al (2009) Upregulation of human DNA binding protein A (dbpA) in gastric cancer cells. Acta Pharmacol Sin 30(10):1436–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu RT et al (2016) RNAi-mediated downregulation of DNA binding protein A inhibits tumorigenesis in colorectal cancer. Int J Mol Med 38(3):703–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yasen M et al (2005) The up-regulation of Y‑box binding proteins (DNA binding protein A and Y‑box binding protein-1) as prognostic markers of hepatocellular carcinoma. Clin Cancer Res 11(20):7354–7361

    Article  CAS  PubMed  Google Scholar 

  26. Hayashi J et al (2002) Somatic mutation and SNP in the promoter of dbpA and human hepatocarcinogenesis. Int J Oncol 21(4):847–850

    CAS  PubMed  Google Scholar 

  27. Nakatsura T et al (2001) Gene cloning of immunogenic antigens overexpressed in pancreatic cancer. Biochem Biophys Res Commun 281(4):936–944

    Article  CAS  PubMed  Google Scholar 

  28. Hohlfeld R et al (2018) Crosstalk between Akt signaling and cold shock proteins in mediating invasive cell phenotypes. Oncotarget 9(27):19039–19049

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang W et al (2016) Antimicrobial peptide LL-37 promotes the proliferation and invasion of skin squamous cell carcinoma by upregulating DNA-binding protein A. Oncol Lett 12(3):1745–1752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tong C et al (2020) Knockdown of DNA-binding protein A enhances the chemotherapy sensitivity of colorectal cancer via suppressing the Wnt/β-catenin/Chk1 pathway. Cell Biol Int 44(10):2075–2085

    Article  CAS  PubMed  Google Scholar 

  31. Yang X‑J et al (2019) Crystal structure of a Y-box binding protein 1 (YB-1)–RNA complex reveals key features and residues interacting with RNA. J Biol Chem 294(28):10998–11010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang J et al (2020) Structural basis of DNA binding to human YB‑1 cold shock domain regulated by phosphorylation. Nucleic Acids Res 48(16):9361–9371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Matsumoto K, Wolffe AP (1998) Gene regulation by Y‑box proteins: coupling control of transcription and translation. Trends Cell Biol 8(8):318–323

    Article  CAS  PubMed  Google Scholar 

  34. Lyabin DN, Eliseeva IA, Ovchinnikov LP (2014) YB‑1 protein: functions and regulation. Wiley Interdiscip Rev RNA 5(1):95–110

    Article  CAS  PubMed  Google Scholar 

  35. Evdokimova VM et al (1998) The major core protein of messenger ribonucleoprotein particles (p50) promotes initiation of protein biosynthesis in vitro. J Biol Chem 273(6):3574–3581

    Article  CAS  PubMed  Google Scholar 

  36. Evdokimova VM et al (1995) The major protein of messenger ribonucleoprotein particles in somatic cells is a member of the Y‑box binding transcription factor family. J Biol Chem 270(7):3186–3192

    Article  CAS  PubMed  Google Scholar 

  37. Minich WB, Maidebura IP, Ovchinnikov LP (1993) Purification and characterization of the major 50-kDa repressor protein from cytoplasmic mRNP of rabbit reticulocytes. Eur J Biochem 212(3):633–638

    Article  CAS  PubMed  Google Scholar 

  38. Hamon L, Budkina K, Pastré D (2022) YB‑1 structure/function relationship in the packaging of mRNPs and consequences for translation regulation and stress granule assembly in cells. Biochemistry 87(1):S20–S31

    CAS  PubMed  Google Scholar 

  39. van Roeyen CRC et al (2013) Cold shock Y‑box protein‑1 proteolysis autoregulates its transcriptional activities. Cell Commun Signal 11(1):63

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hamon L, Budkina K, Pastre D (2022) YB‑1 structure/function relationship in the packaging of mRNPs and consequences for translation regulation and stress granule assembly in cells. Biochemistry (Mosc) 87(1):S20–S93

    Article  CAS  PubMed  Google Scholar 

  41. Perner F et al (2022) YBX1 mediates translation of oncogenic transcripts to control cell competition in AML. Leukemia 36(2):426–437

    Article  CAS  PubMed  Google Scholar 

  42. El-Naggar AM et al (2015) Translational activation of HIF1α by YB‑1 promotes sarcoma metastasis. Cancer Cell 27(5):682–697

    Article  CAS  PubMed  Google Scholar 

  43. Evdokimova V et al (2009) Translational activation of snail1 and other developmentally regulated transcription factors by YB‑1 promotes an epithelial-mesenchymal transition. Cancer Cell 15(5):402–415

    Article  CAS  PubMed  Google Scholar 

  44. Evdokimova V et al (2001) The major mRNA-associated protein YB‑1 is a potent 5′ cap-dependent mRNA stabilizer. EMBO J 20(19):5491–5502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Evdokimova VM, Ovchinnikov LP (1999) Translational regulation by Y‑box transcription factor: involvement of the major mRNA-associated protein, p50. Int J Biochem Cell Biol 31(1):139–149

    Article  CAS  PubMed  Google Scholar 

  46. Minich WB, Ovchinnikov LP (1992) Role of cytoplasmic mRNP proteins in translation. Biochimie 74(5):477–483

    Article  CAS  PubMed  Google Scholar 

  47. Nekrasov MP et al (2003) The mRNA-binding protein YB‑1 (p50) prevents association of the eukaryotic initiation factor eIF4G with mRNA and inhibits protein synthesis at the initiation stage. J Biol Chem 278(16):13936–13943

    Article  CAS  PubMed  Google Scholar 

  48. McKernan CM et al (2022) ABL kinases regulate translation in HER2+ cells through Y‑box-binding protein 1 to facilitate colonization of the brain. Cell Rep 40(9):111268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kosnopfel C et al (2018) YB‑1 expression and phosphorylation regulate tumorigenicity and invasiveness in melanoma by influencing EMT. Mol Cancer Res 16(7):1149–1160

    Article  CAS  PubMed  Google Scholar 

  50. Somasekharan SP et al (2015) YB‑1 regulates stress granule formation and tumor progression by translationally activating G3BP1. J Cell Biol 208(7):913–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chu P‑C et al (2018) Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway. Oncogene 37(25):3440–3455

    Article  CAS  PubMed  Google Scholar 

  52. Koike K et al (1997) Nuclear translocation of the Y‑box binding protein by ultraviolet irradiation. FEBS Lett 417(3):390–394

    Article  CAS  PubMed  Google Scholar 

  53. Rauen T et al (2016) Cold shock protein YB‑1 is involved in hypoxia-dependent gene transcription. Biochem Biophys Res Commun 478(2):982–987

    Article  CAS  PubMed  Google Scholar 

  54. Woolley AG et al (2011) Prognostic association of YB‑1 expression in breast cancers: a matter of antibody. PLoS One 6(6):e20603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yokoyama H et al (2003) Regulation of YB‑1 gene expression by GATA transcription factors. Biochem Biophys Res Commun 303(1):140–145

    Article  CAS  PubMed  Google Scholar 

  56. Uramoto H et al (2002) p73 Interacts with c‑Myc to regulate Y‑box-binding protein‑1 expression. J Biol Chem 277(35):31694–31702

    Article  CAS  PubMed  Google Scholar 

  57. Bommert KS et al (2013) The feed-forward loop between YB‑1 and MYC is essential for multiple myeloma cell survival. Leukemia 27(2):441–450

    Article  CAS  PubMed  Google Scholar 

  58. Shiota M et al (2008) Twist promotes tumor cell growth through YB‑1 expression. Cancer Res 68(1):98–105

    Article  CAS  PubMed  Google Scholar 

  59. Kobayashi S et al (2015) YB‑1 gene expression is kept constant during myocyte differentiation through replacement of different transcription factors and then falls gradually under the control of neural activity. Int J Biochem Cell Biol 68:1–8

    Article  CAS  PubMed  Google Scholar 

  60. Skabkina OV et al (2005) YB‑1 autoregulates translation of its own mRNA at or prior to the step of 40S ribosomal subunit joining. Mol Cell Biol 25(8):3317–3323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Skabkina OV et al (2003) Poly(A)-binding protein positively affects YB‑1 mRNA translation through specific interaction with YB‑1 mRNA. J Biol Chem 278(20):18191–18198

    Article  CAS  PubMed  Google Scholar 

  62. Lyabin DN, Eliseeva IA, Ovchinnikov LP (2012) YB‑1 synthesis is regulated by mTOR signaling pathway. PLoS One 7(12):e52527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lu J et al (2017) YB‑1 expression promotes pancreatic cancer metastasis that is inhibited by microRNA-216a. Exp Cell Res 359(2):319–326

    Article  CAS  PubMed  Google Scholar 

  64. Zhao X et al (2020) Circ-SAR1A promotes renal cell carcinoma progression through miR-382/YBX1 axis. Cancer Manag Res 12:7353–7361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Liu SL, Sui YF, Lin MZ (2016) MiR-375 is epigenetically downregulated due to promoter methylation and modulates multi-drug resistance in breast cancer cells via targeting YBX1. Eur Rev Med Pharmacol Sci 20(15):3223–3229

    PubMed  Google Scholar 

  66. Stratford AL et al (2007) Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y‑box binding protein‑1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy. Breast Cancer Res 9(5):R61

    Article  PubMed  PubMed Central  Google Scholar 

  67. Wu J et al (2006) Disruption of the Y‑box binding protein‑1 results in suppression of the epidermal growth factor receptor and HER‑2. Cancer Res 66(9):4872–4879

    Article  CAS  PubMed  Google Scholar 

  68. Bader AG, Vogt PK (2008) Phosphorylation by Akt disables the anti-oncogenic activity of YB‑1. Oncogene 27(8):1179–1182

    Article  CAS  PubMed  Google Scholar 

  69. Gieseler-Halbach S et al (2017) RSK-mediated nuclear accumulation of the cold-shock Y‑box protein‑1 controls proliferation of T cells and T‑ALL blasts. Cell Death Differ 24(2):371–383

    Article  CAS  PubMed  Google Scholar 

  70. Sutherland BW et al (2005) Akt phosphorylates the Y‑box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells. Oncogene 24(26):4281–4292

    Article  CAS  PubMed  Google Scholar 

  71. Tiwari A et al (2018) Stress-induced phosphorylation of nuclear YB‑1 depends on nuclear trafficking of p90 ribosomal S6 kinase. Int J Mol Sci 19(8):2441. https://doi.org/10.3390/ijms19082441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sogorina EM et al (2022) YB‑1 phosphorylation at serine 209 inhibits its nuclear translocation. Int J Mol Sci 23(1):428

    Article  CAS  Google Scholar 

  73. Mehta S et al (2020) Dephosphorylation of YB‑1 is required for nuclear localisation during G(2) phase of the cell cycle. Cancers (Basel) 12(2):315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jayavelu AK et al (2020) Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature 588(7836):157–163

    Article  PubMed  Google Scholar 

  75. Nöthen T et al (2023) DNA-dependent protein kinase mediates YB‑1 (Y-box binding protein)-induced double strand break repair. ATVB 43(2):300–311

    Article  Google Scholar 

  76. Wang J et al (2016) Therapeutic nuclear shuttling of YB‑1 reduces renal damage and fibrosis. Kidney Int 90(6):1226–1237

    Article  CAS  PubMed  Google Scholar 

  77. Kretov DA et al (2020) Inhibition of transcription induces phosphorylation of YB‑1 at Ser102 and its accumulation in the nucleus. Cells 9(1):104

    Article  CAS  Google Scholar 

  78. Prabhu L et al (2015) Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer. Oncotarget 6(30):29396–29412

    Article  PubMed  PubMed Central  Google Scholar 

  79. Martin M et al (2017) Novel serine 176 phosphorylation of YBX1 activates NF-kappaB in colon cancer. J Biol Chem 292(8):3433–3444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mehta S et al (2020) Critical role for cold shock protein YB‑1 in cytokinesis. Cancers (Basel) 12(9):2473. https://doi.org/10.3390/cancers12092473

    Article  CAS  PubMed  Google Scholar 

  81. El-Naggar AM et al (2019) Class I HDAC inhibitors enhance YB‑1 acetylation and oxidative stress to block sarcoma metastasis. EMBO Rep 20(12):e48375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Frye BC et al (2009) Y‑box protein‑1 is actively secreted through a non-classical pathway and acts as an extracellular mitogen. EMBO Rep 10(7):783–789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim W et al (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44(2):325–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Palicharla VR, Maddika S (2015) HACE1 mediated K27 ubiquitin linkage leads to YB‑1 protein secretion. Cell Signal 27(12):2355–2362

    Article  CAS  PubMed  Google Scholar 

  85. Hartley AV et al (2020) PRMT5-mediated methylation of YBX1 regulates NF-κB activity in colorectal cancer. Sci Rep 10(1):15934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8(12):947–956

    Article  CAS  PubMed  Google Scholar 

  87. Mai RT et al (2022) Sumoylation participates in the regulation of YB-1-mediated mismatch repair deficiency and alkylator tolerance. Am J Cancer Res 12(12):5462–5483

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Chang YW et al (2014) YB‑1 disrupts mismatch repair complex formation, interferes with MutSα recruitment on mismatch and inhibits mismatch repair through interacting with PCNA. Oncogene 33(43):5065–5077

    Article  CAS  PubMed  Google Scholar 

  89. Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418(6901):935–941

    Article  CAS  PubMed  Google Scholar 

  90. Pagano C et al (2017) The tumor-associated YB‑1 protein: new player in the circadian control of cell proliferation. Oncotarget 8(4):6193–6205

    Article  PubMed  Google Scholar 

  91. Liu Q et al (2016) Hyper-O-GlcNAcylation of YB‑1 affects Ser102 phosphorylation and promotes cell proliferation in hepatocellular carcinoma. Exp Cell Res 349(2):230–238

    Article  CAS  PubMed  Google Scholar 

  92. Fujiwara-Okada Y et al (2013) Y‑box binding protein‑1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma. Br J Cancer 108(4):836–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lasham A et al (2012) YB‑1, the E2F pathway, and regulation of tumor cell growth. J Natl Cancer Inst 104(2):133–146

    Article  CAS  PubMed  Google Scholar 

  94. Jurchott K et al (2003) YB‑1 as a cell cycle-regulated transcription factor facilitating cyclin A and cyclin B1 gene expression. J Biol Chem 278(30):27988–27996

    Article  PubMed  Google Scholar 

  95. Tiwari A et al (2020) Blocking Y‑box binding protein‑1 through simultaneous targeting of PI3K and MAPK in triple negative breast cancers. Cancers (Basel) 12(10):2795. https://doi.org/10.3390/cancers12102795

    Article  CAS  PubMed  Google Scholar 

  96. Gaudreault I, Guay D, Lebel M (2004) YB‑1 promotes strand separation in vitro of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities and binds several DNA repair proteins. Nucleic Acids Res 32(1):316–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Toulany M et al (2011) Impact of oncogenic K‑RAS on YB‑1 phosphorylation induced by ionizing radiation. Breast Cancer Res 13(2):R28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lettau K, Zips D, Toulany M (2021) Simultaneous targeting of RSK and AKT efficiently inhibits YB-1-mediated repair of ionizing radiation-induced DNA double-strand breaks in breast cancer cells. Int J Radiat Oncol Biol Phys 109(2):567–580

    Article  PubMed  Google Scholar 

  99. Khozooei S et al (2022) Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells. J Exp Clin Cancer Res 41(1):256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ise T et al (1999) Transcription factor Y‑box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen. Cancer Res 59(2):342–346

    CAS  PubMed  Google Scholar 

  101. Hasegawa SL et al (1991) DNA binding properties of YB‑1 and dbpA: binding to double-stranded, single-stranded, and abasic site containing DNAs. Nucleic Acids Res 19(18):4915–4920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Naumenko KN et al (2020) Regulation of poly(ADP-ribose) polymerase 1 activity by Y‑box-binding protein 1. Biomolecules 10(9):1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Alemasova EE et al (2018) The multifunctional protein YB‑1 potentiates PARP1 activity and decreases the efficiency of PARP1 inhibitors. Oncotarget 9(34):23349–23365

    Article  PubMed  PubMed Central  Google Scholar 

  104. Lettau K et al (2021) Targeting the Y‑box binding protein‑1 axis to overcome radiochemotherapy resistance in solid tumors. Int J Radiat Oncol Biol Phys 111(4):1072–1087

    Article  PubMed  Google Scholar 

  105. Kosnopfel C, Sinnberg T, Schittek B (2014) Y‑box binding protein 1—a prognostic marker and target in tumour therapy. Eur J Cell Biol 93(1):61–70

    Article  CAS  PubMed  Google Scholar 

  106. Toulany M (2023) Targeting K‑Ras-mediated DNA damage response in radiation oncology: current status, challenges and future perspectives. Clin Transl Radiat Oncol 38:6–14

    CAS  PubMed  Google Scholar 

  107. Shinkai K et al (2016) Nuclear expression of Y‑box binding protein‑1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models. Int J Cancer 139(2):433–445

    Article  CAS  PubMed  Google Scholar 

  108. Shiraiwa S et al (2016) Nuclear Y‑box-binding protein‑1 expression predicts poor clinical outcome in stage III colorectal cancer. Anticancer Res 36(7):3781–3788

    CAS  PubMed  Google Scholar 

  109. Ardito F et al (2014) Strong YB‑1 expression predicts liver recurrence following resection for colorectal metastases. J Gastrointest Surg 18(11):1987–1993

    Article  PubMed  Google Scholar 

  110. Zhang Y et al (2015) The expression level and prognostic value of Y‑box binding protein‑1 in rectal cancer. PLoS One 10(3):e119385

    Article  PubMed  PubMed Central  Google Scholar 

  111. Nagasu S et al (2019) Yboxbinding protein 1 inhibits apoptosis and upregulates EGFR in colon cancer. Oncol Rep 41(5):2889–2896

    CAS  PubMed  Google Scholar 

  112. Kashihara M et al (2009) Nuclear Y‑box binding protein‑1, a predictive marker of prognosis, is correlated with expression of HER2/ErbB2 and HER3/ErbB3 in non-small cell lung cancer. J Thorac Oncol 4(9):1066–1074

    Article  PubMed  Google Scholar 

  113. Gessner C et al (2004) Nuclear YB‑1 expression as a negative prognostic marker in nonsmall cell lung cancer. Eur Respir J 23(1):14–19

    Article  CAS  PubMed  Google Scholar 

  114. Jiang L et al (2017) Positive expression of Y‑box binding protein 1 and prognosis in non-small cell lung cancer: a meta-analysis. Oncotarget 8(33):55613–55621

    Article  PubMed  PubMed Central  Google Scholar 

  115. Prior IA, Hood FE, Hartley JL (2020) The frequency of Ras mutations in cancer. Cancer Res 80(14):2969–2974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Raso E (2020) Splice variants of RAS-translational significance. Cancer Metastasis Rev 39(4):1039–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nuevo-Tapioles C, Philips MR (2022) The role of KRAS splice variants in cancer biology. Front Cell Dev Biol 10:1033348

    Article  PubMed  PubMed Central  Google Scholar 

  118. Schlichting I et al (1990) Time-resolved X‑ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature 345(6273):309–315

    Article  CAS  PubMed  Google Scholar 

  119. Milburn MV et al (1990) Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247(4945):939–945

    Article  CAS  PubMed  Google Scholar 

  120. Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294(5545):1299–1304

    Article  CAS  PubMed  Google Scholar 

  121. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129(5):865–877

    Article  CAS  PubMed  Google Scholar 

  122. Saraste M, Sibbald PR, Wittinghofer A (1990) The P‑loop—a common motif in ATP- and GTP-binding proteins. Trends Biochem Sci 15(11):430–434

    Article  PubMed  Google Scholar 

  123. Willumsen BM et al (1984) The p21 ras C‑terminus is required for transformation and membrane association. Nature 310(5978):583–586

    Article  CAS  PubMed  Google Scholar 

  124. Gideon P et al (1992) Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C‑terminal domain of GAP is not sufficient for full activity. Mol Cell Biol 12(5):2050–2056

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hobbs GA, Der CJ, Rossman KL (2016) RAS isoforms and mutations in cancer at a glance. J Cell Sci 129(7):1287–1292

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Cammarata MB et al (2016) Impact of G12 mutations on the structure of K‑Ras probed by ultraviolet photodissociation mass spectrometry. J Am Chem Soc 138(40):13187–13196

    Article  CAS  PubMed  Google Scholar 

  127. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11(11):761–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhang XF et al (1993) Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c‑Raf‑1. Nature 364(6435):308–313

    Article  CAS  PubMed  Google Scholar 

  129. Moodie SA et al (1993) Complexes of Ras.GTP with Raf‑1 and mitogen-activated protein kinase kinase. Science 260(5114):1658–1661

    Article  CAS  PubMed  Google Scholar 

  130. Rodriguez-Viciana P et al (1997) Role of phosphoinositide 3‑OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89(3):457–467

    Article  CAS  PubMed  Google Scholar 

  131. White MA et al (1996) A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J Biol Chem 271(28):16439–16442

    Article  CAS  PubMed  Google Scholar 

  132. Eser S et al (2014) Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer 111(5):817–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jones RP et al (2017) Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer 116(7):923–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Imamura Y et al (2012) Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res 18(17):4753–4763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Buscail L, Bournet B, Cordelier P (2020) Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 17(3):153–168

    Article  CAS  PubMed  Google Scholar 

  136. Goulding RE et al (2020) KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: a systematic literature review and meta-analysis. Cancer Treat Res Commun 24:100200

    Article  PubMed  Google Scholar 

  137. Gurtner K et al (2020) Radioresistance of KRAS/TP53-mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo. Int J Cancer 147(2):472–477

    Article  CAS  PubMed  Google Scholar 

  138. Duldulao MP et al (2013) Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. Ann Surg Oncol 20(7):2166–2171

    Article  PubMed  PubMed Central  Google Scholar 

  139. Mak RH et al (2015) Outcomes by tumor histology and KRAS mutation status after lung stereotactic body radiation therapy for early-stage non-small-cell lung cancer. Clin Lung Cancer 16(1):24–32

    Article  CAS  PubMed  Google Scholar 

  140. Metro G et al (2014) Clinical outcome with platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type non-small-cell lung cancer segregated according to KRAS mutation status. Clin Lung Cancer 15(1):86–92

    Article  CAS  PubMed  Google Scholar 

  141. Lievre A et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995

    Article  CAS  PubMed  Google Scholar 

  142. Benvenuti S et al (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67(6):2643–2648

    Article  CAS  PubMed  Google Scholar 

  143. Forster T et al (2020) Cetuximab in pancreatic cancer therapy: a systematic review and meta-analysis. Oncology 98(1):53–60

    Article  CAS  PubMed  Google Scholar 

  144. Ridouane Y et al (2017) Targeted first-line therapies for advanced colorectal cancer: a Bayesian meta-analysis. Oncotarget 8(39):66458–66466

    Article  PubMed  PubMed Central  Google Scholar 

  145. Smith MJ, Neel BG, Ikura M (2013) NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A 110(12):4574–4579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lu S et al (2016) The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K‑Ras4B. Sci Rep 6:21949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Khrenova MG et al (2014) Modeling the role of G12V and G13V Ras mutations in the Ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate. Biochemistry 53(45):7093–7099

    Article  CAS  PubMed  Google Scholar 

  148. Chen CC et al (2013) Computational analysis of KRAS mutations: implications for different effects on the KRAS p.G12D and p.G13D mutations. PLoS One 8(2):e55793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hunter JC et al (2015) Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res 13(9):1325–1335

    Article  CAS  PubMed  Google Scholar 

  150. Munoz-Maldonado C, Zimmer Y, Medova M (2019) A comparative analysis of individual RAS mutations in cancer biology. Front Oncol 9:1088

    Article  PubMed  PubMed Central  Google Scholar 

  151. Buhrman G, Wink G, Mattos C (2007) Transformation efficiency of RasQ61 mutants linked to structural features of the switch regions in the presence of Raf. Structure 15(12):1618–1629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Haigis KM (2017) KRAS alleles: the devil is in the detail. Trends Cancer 3(10):686–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ihle NT et al (2012) Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst 104(3):228–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hammond DE et al (2015) Differential reprogramming of isogenic colorectal cancer cells by distinct activating KRAS mutations. J Proteome Res 14(3):1535–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Garassino MC et al (2011) Different types of K‑Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol 22(1):235–237

    Article  CAS  PubMed  Google Scholar 

  156. Cook JH et al (2021) The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun 12(1):1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Jia Y et al (2017) Characterization of distinct types of KRAS mutation and its impact on first-line platinum-based chemotherapy in Chinese patients with advanced non-small cell lung cancer. Oncol Lett 14(6):6525–6532

    PubMed  PubMed Central  Google Scholar 

  158. Nadal E et al (2014) KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma. J Thorac Oncol 9(10):1513–1522

    Article  CAS  PubMed  Google Scholar 

  159. Dai M et al (2022) Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection. Front Oncol 12:1074538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Park HE et al (2021) Tumor microenvironment-adjusted prognostic implications of the KRAS mutation subtype in patients with stage III colorectal cancer treated with adjuvant FOLFOX. Sci Rep 11(1):14609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chida K et al (2021) The prognostic impact of KRAS G12C mutation in patients with metastatic colorectal cancer: a multicenter retrospective observational study. Oncologist 26(10):845–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rabara D et al (2019) KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc Natl Acad Sci USA 116(44):22122–22131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Stratford AL et al (2008) Y‑box binding protein‑1 serine 102 is a downstream target of p90 ribosomal S6 kinase in basal-like breast cancer cells. Breast Cancer Res 10(6):R99

    Article  PubMed  PubMed Central  Google Scholar 

  164. Evdokimova V et al (2006) Akt-mediated YB‑1 phosphorylation activates translation of silent mRNA species. Mol Cell Biol 26(1):277–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lee CS et al (2019) MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival. Proc Natl Acad Sci U S A 116(10):4508–4517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Takacs T et al (2020) The effects of mutant Ras proteins on the cell signalome. Cancer Metastasis Rev 39(4):1051–1065

    Article  PubMed  PubMed Central  Google Scholar 

  167. Higuchi M et al (2008) Scaffolding function of PAK in the PDK1-Akt pathway. Nat Cell Biol 10(11):1356–1364

    Article  CAS  PubMed  Google Scholar 

  168. Beeser A et al (2005) Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors. J Biol Chem 280(44):36609–36615

    Article  CAS  PubMed  Google Scholar 

  169. Lu H et al (2017) PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature 550(7674):133–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Zang M, Hayne C, Luo Z (2002) Interaction between active Pak1 and Raf‑1 is necessary for phosphorylation and activation of Raf‑1. J Biol Chem 277(6):4395–4405

    Article  CAS  PubMed  Google Scholar 

  171. Eblen ST et al (2002) Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Mol Cell Biol 22(17):6023–6033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Park ER, Eblen ST, Catling AD (2007) MEK1 activation by PAK: a novel mechanism. Cell Signal 19(7):1488–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wang Z et al (2013) p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner. J Biol Chem 288(27):20093–20099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tang Y et al (2000) The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem 275(13):9106–9109

    Article  CAS  PubMed  Google Scholar 

  175. Zhou GL et al (2003) Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Mol Cell Biol 23(22):8058–8069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. King CC et al (2000) p21-activated kinase (PAK1) is phosphorylated and activated by 3‑phosphoinositide-dependent kinase‑1 (PDK1). J Biol Chem 275(52):41201–41209

    Article  CAS  PubMed  Google Scholar 

  177. Ebi H et al (2013) PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P‑Rex1. Proc Natl Acad Sci U S A 110(52):21124–21129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Thillai K et al (2017) Deciphering the link between PI3K and PAK: an opportunity to target key pathways in pancreatic cancer? Oncotarget 8(8):14173–14191

    Article  PubMed  Google Scholar 

  179. McCarty SK et al (2014) BRAF activates and physically interacts with PAK to regulate cell motility. Endocr Relat Cancer 21(6):865–877

    Article  PubMed  PubMed Central  Google Scholar 

  180. Linardou H et al (2008) Assessment of somatic k‑RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9(10):962–972

    Article  CAS  PubMed  Google Scholar 

  181. Normanno N et al (2009) Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 6(9):519–527

    Article  CAS  PubMed  Google Scholar 

  182. Knickelbein K, Zhang L (2015) Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. Genes Dis 2(1):4–12

    Article  PubMed  Google Scholar 

  183. Eberhard DA et al (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23(25):5900–5909

    Article  CAS  PubMed  Google Scholar 

  184. Sumi S et al (1992) Inhibition of pancreatic adenocarcinoma cell growth by lovastatin. Gastroenterology 103(3):982–989

    Article  CAS  PubMed  Google Scholar 

  185. Kohl NE et al (1994) Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci U S A 91(19):9141–9145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sun J et al (1995) Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K‑Ras mutation and p53 deletion. Cancer Res 55(19):4243–4247

    CAS  PubMed  Google Scholar 

  187. Santillo M et al (1996) Inhibitors of Ras farnesylation revert the increased resistance to oxidative stress in K‑Ras transformed NIH 3T3 cells. Biochem Biophys Res Commun 229(3):739–745

    Article  CAS  PubMed  Google Scholar 

  188. Hunt JT et al (2000) Discovery of (R)-7-cyano‑2,3,4, 5‑tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H‑1,4‑benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem 43(20):3587–3595

    Article  CAS  PubMed  Google Scholar 

  189. Macdonald JS et al (2005) A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs 23(5):485–487

    Article  CAS  PubMed  Google Scholar 

  190. Rao S et al (2004) Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 22(19):3950–3957

    Article  CAS  PubMed  Google Scholar 

  191. Cohen SJ et al (2003) Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 21(7):1301–1306

    Article  CAS  PubMed  Google Scholar 

  192. Adjei AA et al (2003) Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol 21(9):1760–1766

    Article  CAS  PubMed  Google Scholar 

  193. Whyte DB et al (1997) K‑ and N‑Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272(22):14459–14464

    Article  CAS  PubMed  Google Scholar 

  194. Lerner EC et al (1997) Inhibition of the prenylation of K‑Ras, but not H‑ or N‑Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15(11):1283–1288

    Article  CAS  PubMed  Google Scholar 

  195. Martin NE et al (2004) A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L‑778,123 and radiotherapy for locally advanced pancreatic cancer. Clin Cancer Res 10(16):5447–5454

    Article  CAS  PubMed  Google Scholar 

  196. Hahn SM et al (2002) A Phase I trial of the farnesyltransferase inhibitor L‑778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res 8(5):1065–1072

    CAS  PubMed  Google Scholar 

  197. Sepp-Lorenzino L et al (1995) A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 55(22):5302–5309

    CAS  PubMed  Google Scholar 

  198. End DW et al (2001) Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61(1):131–137

    CAS  PubMed  Google Scholar 

  199. Di Paolo A et al (2001) Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells. Br J Cancer 84(11):1535–1543

    Article  CAS  PubMed  Google Scholar 

  200. Song SY et al (2000) K‑Ras-independent effects of the farnesyl transferase inhibitor L‑744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cell. Neoplasia 2(3):261–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ross SJ et al (2017) Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci Transl Med 9(394):eaal5253. https://doi.org/10.1126/scitranslmed.aal5253

    Article  CAS  PubMed  Google Scholar 

  202. Aoki K et al (1995) Liposome-mediated in vivo gene transfer of antisense K‑ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity. Cancer Res 55(17):3810–3816

    CAS  PubMed  Google Scholar 

  203. Tsuchida T et al (1998) Hammerhead ribozyme specifically inhibits mutant K‑ras mRNA of human pancreatic cancer cells. Biochem Biophys Res Commun 253(2):368–373

    Article  CAS  PubMed  Google Scholar 

  204. Kita K et al (1999) Growth inhibition of human pancreatic cancer cell lines by anti-sense oligonucleotides specific to mutated K‑ras genes. Int J Cancer 80(4):553–558

    Article  CAS  PubMed  Google Scholar 

  205. Smakman N et al (2005) Dual effect of Kras(D12) knockdown on tumorigenesis: increased immune-mediated tumor clearance and abrogation of tumor malignancy. Oncogene 24(56):8338–8342

    Article  CAS  PubMed  Google Scholar 

  206. Golan T et al (2015) RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 6(27):24560–24570

    Article  PubMed  PubMed Central  Google Scholar 

  207. Gort E et al (2020) A phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors. J Clin Oncol 38(15):TPS3651–TPS3651

    Article  Google Scholar 

  208. Wee S et al (2009) PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 69(10):4286–4293

    Article  CAS  PubMed  Google Scholar 

  209. Toulany M et al (2016) Dual targeting of PI3K and MEK enhances the radiation response of K‑RAS mutated non-small cell lung cancer. Oncotarget 7(28):43746–43761

    Article  PubMed  PubMed Central  Google Scholar 

  210. Toulany M et al (2014) ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K‑RAS activity to PI3K inhibition. Cancer Biol Ther 15(3):317–328

    Article  CAS  PubMed  Google Scholar 

  211. Shapiro GI et al (2020) Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors. Invest New Drugs 38(2):419–432

    Article  CAS  PubMed  Google Scholar 

  212. Lanman BA et al (2020) Discovery of a covalent inhibitor of KRAS(G12C) (AMG 510) for the treatment of solid tumors. J Med Chem 63(1):52–65

    Article  CAS  PubMed  Google Scholar 

  213. Tanaka N et al (2021) Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov 11(8):1913–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Awad MM et al (2021) Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med 384(25):2382–2393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Blaquier JB, Cardona AF, Recondo G (2021) Resistance to KRAS(G12C) inhibitors in non-small cell lung cancer. Front Oncol 11:787585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Mao Z et al (2022) KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge. Cell Discov 8(1):5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Hallin J et al (2022) Anti-tumor efficacy of a potent and selective non-covalent KRAS(G12D) inhibitor. Nat Med 28(10):2171–2182

    Article  CAS  PubMed  Google Scholar 

  218. Koltun E et al (2021) Abstract 1260: first-in-class, orally bioavailable KRASG12V(ON) tri-complex inhibitors, as single agents and in combinations, drive profound anti-tumor activity in preclinical models of KRASG12V mutant cancers. Cancer Res 81(13):1260–1260

    Article  Google Scholar 

  219. Lasham A et al (2012) YB-1: oncoprotein, prognostic marker and therapeutic target? Biochem J 449(1):11–23

    Article  Google Scholar 

  220. Sangermano F, Delicato A, Calabrò V (2020) Y box binding protein 1 (YB-1) oncoprotein at the hub of DNA proliferation, damage and cancer progression. Biochimie 179:205–216

    Article  CAS  PubMed  Google Scholar 

  221. Serra V et al (2013) RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest 123(6):2551–2563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Maier E et al (2019) Dual targeting of Y‑box binding protein‑1 and Akt inhibits proliferation and enhances the chemosensitivity of colorectal cancer cells. Cancers (Basel) 11(4):562. https://doi.org/10.3390/cancers11040562

    Article  CAS  PubMed  Google Scholar 

  223. Kosnopfel C et al (2017) Human melanoma cells resistant to MAPK inhibitors can be effectively targeted by inhibition of the p90 ribosomal S6 kinase. Oncotarget 8(22):35761–35775

    Article  PubMed  PubMed Central  Google Scholar 

  224. Ushijima M et al (2022) An oral first-in-class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer. Cancer Sci 113(5):1731–1738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Shibata T et al (2020) Targeting phosphorylation of Y‑box–binding protein YBX1 by TAS0612 and everolimus in overcoming antiestrogen resistance. Mol Cancer Ther 19(3):882–894

    Article  CAS  PubMed  Google Scholar 

  226. Tang KJ et al (2016) Focal adhesion kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer. Clin Cancer Res 22(23):5851–5863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Dong S et al (2022) Ceritinib is a novel triple negative breast cancer therapeutic agent. Mol Cancer 21(1):138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Khatri A et al (2019) ABL kinase inhibition sensitizes primary lung adenocarcinomas to chemotherapy by promoting tumor cell differentiation. Oncotarget 10(20):1874–1886

    Article  PubMed  PubMed Central  Google Scholar 

  229. Gupta K et al (2022) Identification of synergistic drug combinations to target KRAS-driven chemoradioresistant cancers utilizing tumoroid models of colorectal adenocarcinoma and recurrent glioblastoma. Front Oncol 12:840241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Khan N et al (2013) Fisetin: a dietary antioxidant for health promotion. Antioxidants Redox Signal 19(2):151–162

    Article  CAS  Google Scholar 

  231. Syed DN et al (2008) Dietary agents for chemoprevention of prostate cancer. Cancer Lett 265(2):167–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Sechi M et al (2018) Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models. Sci Rep 8(1):15726

    Article  PubMed  PubMed Central  Google Scholar 

  233. Khan MI et al (2014) YB‑1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget 5(9):2462–2474

    Article  PubMed  PubMed Central  Google Scholar 

  234. Huang C et al (2022) ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer. Cancer Lett 530:16–28

    Article  CAS  PubMed  Google Scholar 

  235. Lin Y et al (2008) Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 8(7):634–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Reipas KM et al (2013) Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y‑box binding protein‑1 (YB-1). Oncotarget 4(2):329–345. https://doi.org/10.18632/oncotarget.834

    Article  PubMed  PubMed Central  Google Scholar 

  237. Tanaka T et al (2021) 7‑Hydorxyindirubin is capable of specifically inhibiting anticancer drug-induced YB‑1 nuclear translocation without showing cytotoxicity in HepG2 hepatocellular carcinoma cells. Biochem Biophys Res Commun 544:15–21

    Article  CAS  PubMed  Google Scholar 

  238. Ma J‑W et al (2016) Aloe-emodin inhibits HER‑2 expression through the downregulation of Y‑box binding protein‑1 in HER-2-overexpressing human breast cancer cells. Oncotarget 7(37):58915–58930

    Article  PubMed  PubMed Central  Google Scholar 

  239. Chan C et al (2016) Qualitative and quantitative analysis of chemical constituents of centipeda minima by HPLC-QTOF-MS & HPLC-DAD. J Pharm Biomed Anal 125:400–407

    Article  CAS  PubMed  Google Scholar 

  240. Liu YQ et al (2015) Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small molecule inhibitors. Oncotarget 6(33):34953–34967

    Article  PubMed  PubMed Central  Google Scholar 

  241. Li C et al (2018) Sesquiterpene lactone 6‑O-angeloylplenolin reverses vincristine resistance by inhibiting YB‑1 nuclear translocation in colon carcinoma cells. Oncol Lett 15(6):9673–9680

    PubMed  PubMed Central  Google Scholar 

  242. El Hage K et al (2023) Targeting RNA:protein interactions with an integrative approach leads to the identification of potent YBX1 inhibitors. Elife 12:e80387

    Article  PubMed  PubMed Central  Google Scholar 

  243. Tailor D et al (2021) Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer. Cell Chem Biol 28(8):1206–1220.e6

    Article  CAS  PubMed  Google Scholar 

  244. Gunasekaran VP et al (2018) Identification of 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate as a novel inhibitor to Y box binding protein‑1 (YB-1) and its therapeutic actions against breast cancer. Eur J Pharm Sci 116:2–14

    Article  CAS  PubMed  Google Scholar 

  245. Higashi K et al (2011) A novel small compound that promotes nuclear translocation of YB‑1 ameliorates experimental hepatic fibrosis in mice. J Biol Chem 286(6):4485–4492

    Article  CAS  PubMed  Google Scholar 

  246. Law JH et al (2010) Molecular decoy to the Y‑box binding protein‑1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. PLoS One 5(9):e12661

    Article  PubMed  PubMed Central  Google Scholar 

  247. Izumi H et al (2016) Optimal sequence of antisense DNA to silence YB‑1 in lung cancer by use of a novel polysaccharide drug delivery system. Int J Oncol 48(6):2472–2478

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, TO 685/2-3).

Author information

Authors and Affiliations

  1. Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany

    Shayan Khozooei, Soundaram Veerappan &  Mahmoud Toulany

Authors
  1. Shayan Khozooei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soundaram Veerappan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mahmoud Toulany
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahmoud Toulany.

Ethics declarations

Conflict of interest

S. Khozooei, S. Veerappan and M. Toulany declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

S. Khozooei and S. Veerappan share first authorship.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khozooei, S., Veerappan, S. & Toulany, M. YB-1 activating cascades as potential targets in KRAS-mutated tumors. Strahlenther Onkol 199, 1110–1127 (2023). https://doi.org/10.1007/s00066-023-02092-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00066-023-02092-8

Keywords

Search

Navigation