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

Anderson, Gray R

Wardell, Suzanne E

Cakir, Merve

Crawford, Lorin

Leeds, Jim C

Nussbaum, Daniel P

Shankar, Pallavi S

Soderquist, Ryan S

Stein, Elizabeth M

Tingley, Jennifer P

Winter, Peter S

Zieser-Misenheimer, Elizabeth K

Alley, Holly M

Yllanes, Alexander

Haney, Victoria

Blackwell, Kimberly L

McCall, Shannon J

McDonnell, Donald P

Wood, Kris C

United States

2017-01-02T13:21:56Z

2016-12-14

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.

http://www.ncbi.nlm.nih.gov/pubmed/27974663

8/369/369ra175

1946-6242

https://hdl.handle.net/10161/13335

eng

American Association for the Advancement of Science (AAAS)

Sci Transl Med

10.1126/scitranslmed.aae0348

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

Journal article

Wardell, Suzanne E|0000-0002-5792-1447

Nussbaum, Daniel P|0000-0003-3070-6605

McCall, Shannon J|0000-0003-3957-061X

McDonnell, Donald P|0000-0002-7331-4700

Wood, Kris C|0000-0002-5887-2253

http://www.ncbi.nlm.nih.gov/pubmed/27974663

369ra175

369

Basic Science Departments

Biomedical Engineering

Clinical Science Departments

Duke

Duke Cancer Institute

Institutes and Centers

Medicine

Medicine, Endocrinology, Metabolism, and Nutrition

Medicine, Medical Oncology

Pathology

Pharmacology & Cancer Biology

Pratt School of Engineering

Radiation Oncology

School of Medicine

Surgery

Surgery, Surgical Sciences

Published

8