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

TitlePIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.
Publication TypeJournal Article
Year of Publication2016
AuthorsAnderson, Gray R., Suzanne E. Wardell, Merve Cakir, Lorin Crawford, Jim C. Leeds, Daniel P. Nussbaum, Pallavi S. Shankar, Ryan S. Soderquist, Elizabeth M. Stein, Jennifer P. Tingley, Peter S. Winter, Elizabeth K. Zieser-Misenheimer, Holly M. Alley, Alexander Yllanes, Victoria Haney, Kimberly L. Blackwell, Shannon J. McCall, Donald P. McDonnell, and Kris C. Wood
JournalSci Transl Med
Volume8
Issue369
Pagination369ra175
Date Published2016 12 14
ISSN1946-6242
KeywordsAnimals, Apoptosis, bcl-X Protein, Breast Neoplasms, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Combinatorial Chemistry Techniques, DNA Mutational Analysis, Female, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Mice, Mice, Nude, Molecular Targeted Therapy, Mutation, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Transplantation, Proto-Oncogene Proteins c-bcl-2, TOR Serine-Threonine Kinases
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-X) 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-X This dual dependence on BCL-X 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-X/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-X 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-X and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-X may be effective in tumors lacking PIK3CA mutations.

DOI10.1126/scitranslmed.aae0348
Alternate JournalSci Transl Med
Original PublicationPIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.
PubMed ID27974663
PubMed Central IDPMC5626456
Grant ListK12 HD043446 / HD / NICHD NIH HHS / United States
P01 CA142538 / CA / NCI NIH HHS / United States
R01 DK048807 / DK / NIDDK NIH HHS / United States
R37 DK048807 / DK / NIDDK NIH HHS / United States