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

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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Citation

Published Version (Please cite this version)

10.1126/scitranslmed.aae0348

Publication Info

Anderson, Gray R, Suzanne E Wardell, Merve Cakir, Lorin Crawford, Jim C Leeds, Daniel P Nussbaum, Pallavi S Shankar, Ryan S Soderquist, et al. (2016). PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation. Sci Transl Med, 8(369). p. 369ra175. 10.1126/scitranslmed.aae0348 Retrieved from https://hdl.handle.net/10161/13335.

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Scholars@Duke

Wardell

Suzanne E Wardell

Assistant Research Professor of Pharmacology & Cancer Biology

Throughout my career in science, my work has focused in aspects of steroid hormone (progesterone, estrogen, or androgen) receptor activity in breast and prostate cancers. These interests include not only mechanistic studies of receptor activity in treatment naive tumors, but also the role of these receptors in the evolution of resistance to current therapies.

Despite the development of improved therapies, breast cancer remains a leading cause of mortality in women. While a majority of breast cancers are estrogen receptor (ER) positive and respond to endocrine therapies such as tamoxifen or aromatase inhibitors, as many as 50% of patients experience relapse and progression. Recent data has confirmed continued reliance of these cancers on ER signaling, validating this receptor as a therapeutic target even in a relapsed/metastatic setting. The focus of a majority of my work in breast cancer has been the mechanistic evaluation of methods to target ER activity in this setting of resistance, either through the development of improved receptor antagonists or through the identification of targets downstream of, or impinging upon, ER activity that can serve as secondary targets in this setting. 

Similarly, the androgen receptor (AR) remains a therapeutic target in prostate cancer throughout treatment progression to end stage prostate cancer. Although several AR antagonists have been developed and approved for the treatment of prostate cancer, AR overexpression, as well as mutation and/or truncation, are observed clinically and have been shown mechanistically to render the current AR antagonists ineffective in the advanced prostate cancer setting. As with our work in breast cancer, we have identified pathways downstream of AR that are essential to prostate cancer progression, and our current work is intended to devise treatment regimens that will be effective in lieu of, or together with, AR antagonists.

In my role as a research assistant professor, I have conducted several animal studies evaluating next-to-clinic therapeutics in clinically predictive models of advanced breast and prostate cancer that I have developed throughout the past several years of studies. The entry of some of these therapeutics, or of mechanistically related molecules, into clinical trials in these patient populations validates this approach.

Nussbaum

Daniel Philip Nussbaum

Assistant Professor of Surgery
Blackwell

Kimberly Lynn Blackwell

Adjunct Professor in the Department of Medicine

Breast cancer angiogenesis
Breast cancer in younger women
Hormonal therapy
Neoadjurant therapy for breast cancer

Current Clinical Investigations

Principal Investigator, A Phase I-II Study of Neoadjuvant Evacet/Paclitaxel/Hyperthermia in Locally Advanced Breast Cancer Patients.

Investigator, Development of Screening Markers for Breast Cancer using Circulating Immune Complexes: Collaborative Study with Diagen Medical Technologies.

Principal Investigator, Use of Plasma D-Dimer as a Predictive Marker in Colorectal Carcinoma: Correlative Science Study with Genentech, Inc.

Principal Investigator, A randomized, Phase II study of gabapentin or glutamine to prevent the peripheral neuropathy/myalgia associated with weekly taxol administration in metastatic breast and lung cancer.

Investigator, A Phase 2, Randomized, Double-Masked, Multicenter Study of Two Dose Levels of ERA-923 for the treatment of Metastatic Breast Cancer in Postmenopausal Women who have failed Tamoxifen therapy. Genetics Institute.

Investigator, A Phase I Study of Combined Doxil/Hyperthermia in Stage IV Breast Cancer.


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