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Review
. 2019 Apr;9(4):482-491.
doi: 10.1158/2159-8290.CD-18-1175. Epub 2019 Mar 13.

Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors

Ariella B Hanker  1 , Virginia Kaklamani  2 , Carlos L Arteaga  3
Affiliations
Review

Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors

Ariella B Hanker et al. Cancer Discov. 2019 Apr.

Abstract

The PI3K pathway is mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival, making it a rational therapeutic target. Until recently, however, results from clinical trials with PI3K inhibitors in solid tumors have been largely disappointing. Here, we describe several factors that have limited the success of these agents, including the weak driver oncogenic activity of mutant PI3K, suboptimal patient selection in trials, drug-related toxicities, feedback upregulation of compensatory mechanisms when PI3K is blocked, increased insulin production upon PI3Kα inhibition, lack of mutant-specific inhibitors, and a relative scarcity of studies using combinations with PI3K antagonists. We also suggest strategies to improve the impact of these agents in solid tumors. Despite these challenges, we are optimistic that isoform-specific PI3K inhibitors, particularly in combination with other agents, may be valuable in treating appropriately selected patients with PI3K-dependent tumors. SIGNIFICANCE: Despite the modest clinical activity of PI3K inhibitors in solid tumors, there is an increasing understanding of the factors that may have limited their success. Strategies to ameliorate drug-related toxicities, use of rational combinations with PI3K antagonists, development of mutant-selective PI3K inhibitors, and better patient selection should improve the success of these targeted agents against solid tumors.

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Conflict of interest statement

Conflict of interest disclosure statement: A.B. Hanker receives grant support from Takeda. V. Kaklamani receives grant support from Eisai; she is a speaker for Novartis, Eisai, Genentech, Pfizer, and Genomic Health; she is a consultant for Novartis, Athenex, Eisai, and Amgen. C.L. Arteaga receives grant support from Pfizer, Eli Lilly, Radius, and Takeda; he has served or serves in advisory roles to Symphogen, Daiichi Sankyo, TAIHO Oncology, Novartis, Merck, PUMA Biotechnology, Eli Lilly, Radius, Sanofi, OrigiMed, ABBVIE, and H3Biomedicine; he holds stock options in Provista and Y-Trap. He serves in the Scientific Advisory Board of the Komen Foundation.

Figures

Figure 1.
Figure 1.. Adaptive upregulation of compensatory pathways limits the efficacy of PI3K inhibitors.
Several adaptive feedback mechanisms that limit complete suppression of PIP3 and the cellular response to PI3K inhibitors have been described. These include FOXO-mediated de-repression of RTKs and de-repression of IRS1, leading to partial maintenance of PIP3. In ER+ breast cancer cells, treatment with PI3K inhibitors induces ERα transcriptional activity via the histone methyltransferase KMT2D.
Figure 2.
Figure 2.. Insulin feedback limits the anti-tumor effects of PI3K inhibitors.
PI3Kα mediates insulin-driven glucose uptake in muscle, liver, and fat cells. Upon inhibition of PI3Kα, glucose uptake in muscle and fat cells is blocked, and breakdown of liver glycogen is stimulated, thus resulting in hyperglycemia. Elevated glucose levels, in turn, drive insulin release from the pancreas. Elevated insulin levels activate the insulin receptor (InsR) in tumor cells, leading to enhanced stimulation of PI3K, and limiting the effects of PI3K inhibitors. Tumors with PIK3CA mutations would be particularly sensitive to insulin. In preclinical models, SGLT2 inhibitors or a ketogenic diet restore homeostasis and synergize with PI3K inhibitors to reduce tumor growth. Red arrows indicate response to PI3K inhibitors.
See this image and copyright information in PMC

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References

    1. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 2015;15(1):7–24 doi 10.1038/nrc3860. - DOI - PMC - PubMed
    1. Mayer IA, Arteaga CL. The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu Rev Med 2016;67:11–28 doi 10.1146/annurev-med-062913-051343. - DOI - PubMed
    1. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nature reviews Clinical oncology 2018;15(5):273–91 doi 10.1038/nrclinonc.2018.28. - DOI - PubMed
    1. Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer discovery 2016;6(10):1090–105 doi 10.1158/2159-8290.Cd-16-0716. - DOI - PMC - PubMed
    1. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14(12):1351–6 doi nm.1890 [pii] 10.1038/nm.1890. - DOI - PMC - PubMed

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