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Nat Commun DOI:10.1038/s41467-020-16170-3

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer.

Publication TypeJournal Article
Year of Publication2020
AuthorsGe, JY, Shu, S, Kwon, M, Jovanović, B, Murphy, K, Gulvady, A, Fassl, A, Trinh, A, Kuang, Y, Heavey, GA, Luoma, A, Paweletz, C, Thorner, AR, Wucherpfennig, KW, Qi, J, Brown, M, Sicinski, P, McDonald, TO, Pellman, D, Michor, F, Polyak, K
JournalNat Commun
Volume11
Issue1
Pages2350
Date Published2020 May 11
ISSN2041-1723
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.

DOI10.1038/s41467-020-16170-3
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32393766?dopt=Abstract

Alternate JournalNat Commun
PubMed ID32393766
PubMed Central IDPMC7214447
Grant ListR35 CA197623 / CA / NCI NIH HHS / United States
P01 CA080111 / CA / NCI NIH HHS / United States
F30 CA228208 / CA / NCI NIH HHS / United States
CA168504 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
CA228208 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
CA202634 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
P50 CA168504 / CA / NCI NIH HHS / United States
R01 CA202634 / CA / NCI NIH HHS / United States
U54 CA193461 / CA / NCI NIH HHS / United States
CA193461 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /