PMID- 27974663 OWN - NLM STAT- MEDLINE DCOM- 20171229 LR - 20220316 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 8 IP - 369 DP - 2016 Dec 14 TI - PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation. PG - 369ra175 AB - 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(L)) 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(L) This dual dependence on BCL-X(L) 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(L)/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(L) 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(L) and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-X(L) may be effective in tumors lacking PIK3CA mutations. CI - Copyright (c) 2016, American Association for the Advancement of Science. FAU - Anderson, Gray R AU - Anderson GR AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Wardell, Suzanne E AU - Wardell SE AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Cakir, Merve AU - Cakir M AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. AD - Program in Computational Biology and Bioinformatics, Duke University, Durham, NC 27708, USA. FAU - Crawford, Lorin AU - Crawford L AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. AD - Department of Statistical Science, Duke University, Durham, NC 27708, USA. FAU - Leeds, Jim C AU - Leeds JC AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Nussbaum, Daniel P AU - Nussbaum DP AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. AD - Department of Surgery, Duke University, Durham, NC 27710, USA. FAU - Shankar, Pallavi S AU - Shankar PS AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Soderquist, Ryan S AU - Soderquist RS AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Stein, Elizabeth M AU - Stein EM AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Tingley, Jennifer P AU - Tingley JP AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Winter, Peter S AU - Winter PS AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. AD - Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA. FAU - Zieser-Misenheimer, Elizabeth K AU - Zieser-Misenheimer EK AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Alley, Holly M AU - Alley HM AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Yllanes, Alexander AU - Yllanes A AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Haney, Victoria AU - Haney V AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Blackwell, Kimberly L AU - Blackwell KL AD - Department of Medicine/Oncology, Duke University, Durham, NC 27710, USA. FAU - McCall, Shannon J AU - McCall SJ AD - Department of Pathology, Duke University, Durham, NC 27710, USA. FAU - McDonnell, Donald P AU - McDonnell DP AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. FAU - Wood, Kris C AU - Wood KC AD - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. kris.wood@duke.edu. LA - eng GR - K12 HD043446/HD/NICHD NIH HHS/United States GR - P01 CA142538/CA/NCI NIH HHS/United States GR - R01 DK048807/DK/NIDDK NIH HHS/United States GR - R37 DK048807/DK/NIDDK NIH HHS/United States PT - Journal Article PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (BCL2 protein, human) RN - 0 (BCL2L1 protein, human) RN - 0 (MCL1 protein, human) RN - 0 (Myeloid Cell Leukemia Sequence 1 Protein) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-X Protein) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Apoptosis MH - Breast Neoplasms/*drug therapy/genetics MH - Cell Line, Tumor MH - Class I Phosphatidylinositol 3-Kinases/*genetics MH - Combinatorial Chemistry Techniques MH - DNA Mutational Analysis MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - MAP Kinase Signaling System MH - Mice MH - Mice, Nude MH - *Molecular Targeted Therapy MH - Mutation MH - Myeloid Cell Leukemia Sequence 1 Protein/*metabolism MH - Neoplasm Transplantation MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - bcl-X Protein/genetics PMC - PMC5626456 MID - NIHMS907644 EDAT- 2016/12/16 06:00 MHDA- 2017/12/30 06:00 PMCR- 2017/10/03 CRDT- 2016/12/16 06:00 PHST- 2016/07/20 00:00 [received] PHST- 2016/09/06 00:00 [revised] PHST- 2016/10/05 00:00 [accepted] PHST- 2016/12/16 06:00 [entrez] PHST- 2016/12/16 06:00 [pubmed] PHST- 2017/12/30 06:00 [medline] PHST- 2017/10/03 00:00 [pmc-release] AID - 8/369/369ra175 [pii] AID - 10.1126/scitranslmed.aae0348 [doi] PST - ppublish SO - Sci Transl Med. 2016 Dec 14;8(369):369ra175. doi: 10.1126/scitranslmed.aae0348.