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자연과학대학
생명과학전공
Journal papers
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Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer
Title
Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer
Authors
Ge J.Y.
;
Shu S.
;
Kwon M.
;
Jovanović B.
;
Murphy K.
;
Gulvady A.
;
Fassl A.
;
Trinh A.
;
Kuang Y.
;
Heavey G.A.
;
Luoma A.
;
Paweletz C.
;
Thorner A.R.
;
Wucherpfennig K.W.
;
Qi J.
;
Brown M.
;
Sicinski P.
;
McDonald T.O.
;
Pellman D.
;
Michor F.
;
Polyak K.
Ewha Authors
권미정
SCOPUS Author ID
권미정
Issue Date
2020
Journal Title
Nature Communications
ISSN
2041-1723
Citation
Nature Communications vol. 11, no. 1
Publisher
Nature Research
Indexed
SCIE; SCOPUS
Document Type
Article
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. © 2020, The Author(s).
DOI
10.1038/s41467-020-16170-3
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