@article{93997bc353714eaa95b0d387ce3132cc,
title = "BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer",
abstract = "Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.",
keywords = "BRD4, CP: Cancer, MCL1, adaptive responses, apoptosis, bioinformatics, combination therapy, drug resistance, fatty acid pathway, lipids, network models, Up-Regulation, Fatty Acids, Humans, Lipids, Myeloid Cell Leukemia Sequence 1 Protein/metabolism, Cell Line, Tumor, Female, ErbB Receptors/metabolism, Breast Neoplasms/drug therapy",
author = "Gonghong Yan and Augustin Luna and Heping Wang and Behnaz Bozorgui and Xubin Li and Maga Sanchez and Zeynep Dereli and Nermin Kahraman and Goknur Kara and Xiaohua Chen and Caishang Zheng and Daniel McGrail and Nidhi Sahni and Yiling Lu and Ozgun Babur and Murat Cokol and Bora Lim and Bulent Ozpolat and Chris Sander and Mills, {Gordon B.} and Anil Korkut",
note = "Funding Information: This work is supported by grants from OCRA Collaborative Research Award (A.K. and G.B.M.); US NCI grants U24CA210950 (G.B.M.), P50CA217685 (G.B.M.), P30 CA016672 (MDACC Support Grant, the Bioinformatics Shared Resource ; A.K.), and U01CA217842 (A.K. and G.B.M.); ICI Fund (A.K.); NIGMS P41 GM103504 (C.S.); CPRIT High-Impact/High-Risk Award ( RP170640 ; A.K.); a kind gift from the Miriam and Sheldon Adelson Medical Research Foundation (G.B.M.); SAC110052 from the Susan G. Komen Foundation (G.B.M.); and BCRF-18-110 from the Komen Foundation ( PDF17483544 ; D.M.). Confocal microscopy experiments are performed at the MDACC Advanced Microscopy Facility funded by NIH S10 RR029552 . N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 and a recipient of Early Career Award by Ovarian Cancer Research Alliance (grant 649968 ). Funding Information: This work is supported by grants from OCRA Collaborative Research Award (A.K. and G.B.M.); US NCI grants U24CA210950 (G.B.M.), P50CA217685 (G.B.M.), P30 CA016672 (MDACC Support Grant, the Bioinformatics Shared Resource; A.K.), and U01CA217842 (A.K. and G.B.M.); ICI Fund (A.K.); NIGMS P41 GM103504 (C.S.); CPRIT High-Impact/High-Risk Award (RP170640; A.K.); a kind gift from the Miriam and Sheldon Adelson Medical Research Foundation (G.B.M.); SAC110052 from the Susan G. Komen Foundation (G.B.M.); and BCRF-18-110 from the Komen Foundation (PDF17483544; D.M.). Confocal microscopy experiments are performed at the MDACC Advanced Microscopy Facility funded by NIH S10 RR029552. N.S. is a CPRIT Scholar in Cancer Research with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator Grant RR160021 and a recipient of Early Career Award by Ovarian Cancer Research Alliance (grant 649968). G.Y.: in vitro experiments, conceptualization, data analysis, writing original manuscript; A.L.: computational methodology, analysis, writing original manuscript; H.W.: computational methodology; B.B.: data analysis, statistics, manuscript editing; X.L.: transcriptomic data analysis; M.S.: immunohistochemistry (IHC) experiments; Z.D.: IHC experiments, confocal microscopy; N.K.: in vivo experiments, data analysis; G.K.: in vivo experiments; X.C.: in vitro cell viability measurements, RPPA measurements; C.Z.: qPCR; D.M.: analysis of ChIP-seq data, manuscript editing; N.S.: analysis of ChIP-seq data, manuscript editing; Y.L.: in vitro cell viability and RPPA measurements; O.B.: computational methodology, analysis, writing original manuscript; M.C.: data analysis, writing original manuscript; B.L.: data analysis, editing manuscript; B.O.: in vivo experiments, provided reagents, data analysis; C.S.: conceptualization, editing manuscript; G.B.M.: conceptualization, editing manuscript, reagents, RPPA experiments; A.K.: conceptualization, data analysis and interpretation, methodology, writing original manuscript. G.B.M. SAB/consultant: AstraZeneca, Chrysallis Biotechnology, ImmunoMET, Ionis, Lilly, Nuevolution, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda; stock/options/financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda; licensed technology HRD assay to Myriad Genetics; DSP patent with Nanostring. Z.D.: shareholder in Vivoz Biolabs, LLC. M.C.: paid employee of Axcella Health. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = sep,
day = "13",
doi = "10.1016/j.celrep.2022.111304",
language = "English (US)",
volume = "40",
pages = "111304",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}