@article{4d266263dfb64af697e10fbe9b803346,
title = "Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer",
abstract = "BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.",
author = "Ge, {Jennifer Y.} and Shaokun Shu and Mijung Kwon and Bojana Jovanovi{\'c} and Katherine Murphy and Anushree Gulvady and Anne Fassl and Anne Trinh and Yanan Kuang and Heavey, {Grace A.} and Adrienne Luoma and Cloud Paweletz and Thorner, {Aaron R.} and Wucherpfennig, {Kai W.} and Jun Qi and Myles Brown and Piotr Sicinski and McDonald, {Thomas O.} and David Pellman and Franziska Michor and Kornelia Polyak",
note = "Funding Information: We thank members of our laboratories for their critical reading of this manuscript and useful discussions. This work was supported by the National Cancer Institute PSOC U54 CA193461 (F.M. and K.P.), F30 CA228208 (J.Y.G.), P01 CA080111 (K.P., M.B., and P.S.), R35 CA197623 (K.P.), SPORE P50 CA168504 (K.P.), and R01 CA202634 (P.S.), the Helen Gurley Brown Presidential Initiative Award (A.T.), the Department of Defense Breakthrough Fellowship Award W81XWH-18-1-0027 (B.J.), the Susan G. Komen Foundation (S.S.), and the Ludwig Center at Harvard (K.P., F.M., M.B., D.P.). Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-16170-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}