title: 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-XLThis dual dependence on BCL-XLand 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-XLalso 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-XLand the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XLmay be effective in tumors lacking PIK3CA mutations.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Gray R
authors.initials: GR
authors.lastname: Anderson
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Program in Computational Biology and Bioinformatics, Duke University, Durham, NC 27708, USA.
authors.forename: Merve
authors.initials: M
authors.lastname: Cakir
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Department of Statistical Science, Duke University, Durham, NC 27708, USA.
authors.forename: Lorin
authors.initials: L
authors.lastname: Crawford
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Leeds
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Department of Surgery, Duke University, Durham, NC 27710, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Nussbaum
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Pallavi S
authors.initials: PS
authors.lastname: Shankar
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Soderquist
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Stein
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Tingley
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Winter
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Zieser-Misenheimer
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Alley
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Yllanes
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Haney
authors.affiliation: Department of Medicine/Oncology, Duke University, Durham, NC 27710, USA.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
authors.affiliation: Department of Pathology, Duke University, Durham, NC 27710, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: McCall
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. kris.wood@duke.edu.
authors.forename: Kris C
authors.initials: KC
authors.lastname: Wood
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020650:Combinatorial Chemistry Techniques; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D058570:TOR Serine-Threonine Kinases