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Review
. 2024 Aug;65(2):80.
doi: 10.3892/ijo.2024.5668. Epub 2024 Jul 12.

Targeting drug resistance in glioblastoma (Review)

Jonathan H Sherman  1 , Adam Bobak  2 , Tasneem Arsiwala  3 , Paul Lockman  3 , Sonikpreet Aulakh  4
Affiliations
Review

Targeting drug resistance in glioblastoma (Review)

Jonathan H Sherman et al. Int J Oncol. 2024 Aug.

Abstract

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor‑treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood‑brain barrier, blood tumor barrier, glioma stem‑like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.

Keywords: genetic heterogeneity; glioblastoma; radiation therapy; recurrence; resistance; therapeutics.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Clinically relevant dysregulated pathways in GBM. EGFR, PDGFRA and MET are some of the most common RTK receptors mutated and/or amplified in GBM. These mutations and/or amplifications alter downstream signaling pathways responsible for tumor growth and survival. GBMs with these receptor modifications can activate the RAS signaling pathway, promoting cell proliferation and survival while retaining mutations in the inhibitory protein of RAS, NF1. PI3K signaling is also upregulated by these receptor alterations, while also harboring alterations in the signaling pathway itself. In its wild-type form, PTEN inhibits conversion of PIP2 to PIP3. When mutated, it activates a downstream cascade of signaling pathways. Increase in Akt activity inhibits FOXO, assisting in uncontrolled cell proliferation. While Mouse Double Minute 2 (MDM2) has an increase in activity due to the increase in Akt activity, MDM2 is also amplified in ~14% of GBMs. MDM2 is typically inhibited by CDKN2A in response to activated oncogenic genes/signals, but CDKN2A is mutated in ~50% of GBMs. MDM2 inhibits p53 while the p53 gene itself is identified to have mutations in ~28% of GBMs. The inhibition of p53 due to mutations and/or increased activity of MDM2 prevents p53 from sending cells into apoptosis, leading to tumor growth and survival. The protein mTOR is also activated by Akt which promotes the cell cycle, leading to phosphorylation of Rb, which allows activation of E2F, thus promoting cell proliferation. The Rb signaling pathway is also known to be altered in almost 80% of GBMs. The image was created using BioRender.com. GBM, glioblastoma; RTK, receptor tyrosine kinase; NF1, neurofibromin 1; PTEN, phosphatase and tensin homolog; Rb, retinoblastoma.
Figure 2
Figure 2
MGMT promoter methylation status contributes to the sensitivity of GBM cells to TMZ. TMZ adds a methyl group to the O6 position on guanine. In tumors where the MGMT promoter is unmethylated, there is active MGMT, and the methyl groups will be removed, preventing DNA damage. The presence of MGMT leads to GBM cells that are resistant to TMZ. In tumors where the MGMT promoter is hypermethylated, there is an absence of MGMT, causing the guanine residues to stay methylated. This leads to the recruitment of DNA repair enzymes or direct signals for apoptosis. If repair enzymes fail to remove O6meG or the cells are not directly signaling for apoptosis, O6meG can lead to mismatch pairing with thymine residues leading to recruitment of MMR. If MMR is unsuccessful, DSBs can occur, leading to homologous recombination, non-homologous end-joining or cell death. The image was created using BioRender.com. MGMT, methylguanine-DNA methyltransferase; TMZ, temozolomide; GBM, glioblastoma; MMR, mismatch repair enzymes; DSBs, double-strand breaks.
Figure 3
Figure 3
Pathways involved in radiation therapy resistance in GBM. Radiation treatment produces ROS that cause DNA damage and ultimately result in cell death. GBM has hypoxic regions that can be observed on MRI. Hypoxic regions cause a decrease in oxygen thus preventing the formation of ROS, which leads to futile cell death. Within GBM tumors, there are GSCs that have stem-like properties. Radiation treatment eliminates differentiated cells, while GSCs are radioresistant. Tumor heterogeneity is a leading contributor in treatment resistance in GBM. Through several permutations, tumors have multiple ways of becoming radioresistant. The image was created using BioRender.com. GBM, glioblastoma; ROS, reactive oxygen species; GSCs, glioma stem cells; PTEN, phosphatase and tensin homolog.
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References

    1. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: A clinical review. JAMA. 2013;310:1842–1850. doi: 10.1001/jama.2013.280319. - DOI - PubMed
    1. Hale JS, Sinyuk M, Rich JN, Lathia JD. Decoding the cancer stem cell hypothesis in glioblastoma. CNS Oncol. 2013;2:319–330. doi: 10.2217/cns.13.23. - DOI - PMC - PubMed
    1. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Amp Prev. 2014;23:1985–1996. doi: 10.1158/1055-9965.EPI-14-0275. - DOI - PMC - PubMed
    1. Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee ShU. Glioblastoma Multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 2017;18:3–9. - PMC - PubMed
    1. Alexander BM, Cloughesy TF. Adult Glioblastoma. J Clin Oncol. 2017;35:2402–2409. doi: 10.1200/JCO.2017.73.0119. - DOI - PubMed

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