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

Year: 2020
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.
DOI: 10.1038/s41467-020-16170-3
Authors: Jennifer Y. Ge, Shaokun Shu, Mijung Kwon, Bojana Jovanović, Katherine Murphy, Anushree Gulvady, Anne Fassl, Anne Trinh, Yanan Kuang, Grace A. Heavey, Adrienne Luoma, Cloud Paweletz, Aaron R. Thorner, Kai W. Wucherpfennig, Jun Qi, Myles Brown, Piotr Sicinski, Thomas O. McDonald, David Pellman, Franziska Michor, Kornelia Polyak
Institutions: Harvard University, Harvard–MIT Division of Health Sciences and Technology, Dana-Farber Cancer Institute, Massachusetts Institute of Technology, Peking University Cancer Hospital, Ewha Womans University, Broad Institute, Dana-Farber/Harvard Cancer Center
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $5,380
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Susan G. Komen for the Cure, Susan G. Komen, National Institutes of Health, Ludwig Center at Harvard, National Cancer Institute
Awards: Evolution and Treatment Response of Brain, Breast, and Hematologic Malignancies, G1079167425, G142349785, G1733809635, Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer, Optimal BET inhibitor combination therapies in triple negative breast cancer, G3261725791, G3352250835, G340051698, G3973866091, G4007664736, G4119534169, G4476719350, G4627906632, G483504939, G5442596997, Novel functions of D-type and E-type cyclins in normal and in cancer cells, G6813750471, G7215281656, G7276751697, G7797790202, G784047723, G7899173603, G8166743225, Polyploidy, Aneuploidy and Genome Stability
OpenAlex ID: W3022464154
FWCI: 6.27
Cites: 67
Cited by: 96
Related to: 10