Editors' ChoiceCancer

Inhibit PIM to inhibit PI3K

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Sci. Signal.  11 Oct 2016:
Vol. 9, Issue 449, pp. ec237
DOI: 10.1126/scisignal.aal1638

Mutations in the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K, encoded by PIK3CA) are common in breast cancer. Drugs inhibiting PI3K show efficacy in a small proportion of patients; some tumors are intrinsically resistant, whereas others become resistant. Le et al. found that another kinase, proviral insertion site in murine leukemia virus (PIM), maintains the activity of downstream effectors of the PI3K pathway and that cotargeting PIM may be effective in patients that show resistance to PI3K inhibitors. A large gain-of-function screen in cultured PI3K-mutant, luminal A-type breast cancer cells identified genes encoding isoforms of PIM as promoting resistance to the PI3K inhibitor BYL719. Overexpression of PIM1 (more so than that of PIM2 or PIM3) decreased the potency of BYL719 and other PI3K pathway inhibitors in various types of breast cancer cells. Cultures of PI3K-mutant breast cancer cells that were resistant to BYL719 had greater abundance of all three PIM isoforms than the parental cultures. Drug-resistant cultured cells with endogenously or enforced high PIM1 abundance also exhibited phosphorylation of proteins downstream of the kinase AKT in the PI3K pathway, indicating increased activity of the mechanistic target of rapamycin (mTOR) pathway and antiapoptotic signaling. Indeed, Treating PI3K-mutant, PIM1-abundant cells with a single-agent PIM inhibitors (LGH447 or AZD1208) had little or no effect on mTOR pathway activity or cell proliferation, whereas combining a PIM inhibitor with BYL719 substantially suppressed both processes. Breast tumor biopsies from some patients that received BYL719 therapy had a similar gene expression profile to that in PIM1-overexpressing T47D breast cancer cells. Analysis of biopsies from treatment-naïve patients indicated that PIM family gene amplifications and PIK3CA mutations or amplifications are mutually exclusive. PIM inhibitors are already in clinical development for hematological cancers; this study suggests their use may be extended to some breast cancer patients. Additionally, several PI3K inhibitor resistance genes found in the authors’ screen (such as DYRK1B and NUDT3) are associated with obesity and diabetes; thus the results of the screen also provide a connection between aberrant metabolism to PI3K inhibitor resistance. The new therapeutic avenues suggested by this study may lead to better clinical outcomes for patients with PI3K-mutant breast cancer.

X. Le, R. Antony, P. Razavi, D. J. Treacy, F. Luo, M. Ghandi, P. Castel, M. Scaltriti, J. Baselga, L. A. Garraway, Systematic functional characterization of resistance to PI3K inhibition in breast cancer. Cancer Discov. 6, 1134–1147 (2016). [PubMed]

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