Research ArticleCancer

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

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Science Translational Medicine  14 Dec 2016:
Vol. 8, Issue 369, pp. 369ra175
DOI: 10.1126/scitranslmed.aae0348

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Sneak attack on breast cancer’s defense

The usual goal of cancer treatment is to kill malignant cells, not just slow down their growth. A class of drugs called BH3 mimetics serves this purpose by inhibiting antiapoptotic proteins and thus helping drive the cells toward apoptosis (programmed cell death). MCL-1 is an antiapoptotic protein that is not targeted by currently bioavailable BH3 mimetics, and it is often responsible for resistance to these drugs. Anderson et al. have discovered that breast cancers with the commonly observed PIK3CA mutations can be treated with mTOR inhibitors to suppress MCL-1, leaving the cells vulnerable to BH3 mimetics and subsequent induction of apoptosis, both directly and in combination with chemotherapy.

Abstract

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma–extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia–1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL. This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

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