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

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 () and Kornelia Polyak ()
Additional contact information
Jennifer Y. Ge: Dana-Farber Cancer Institute
Shaokun Shu: Dana-Farber Cancer Institute
Mijung Kwon: Dana-Farber Cancer Institute
Bojana Jovanović: Dana-Farber Cancer Institute
Katherine Murphy: Dana-Farber Cancer Institute
Anushree Gulvady: Dana-Farber Cancer Institute
Anne Fassl: Dana-Farber Cancer Institute
Anne Trinh: Dana-Farber Cancer Institute
Yanan Kuang: Dana-Farber Cancer Institute
Grace A. Heavey: Dana-Farber Cancer Institute
Adrienne Luoma: Dana-Farber Cancer Institute
Cloud Paweletz: Dana-Farber Cancer Institute
Aaron R. Thorner: Dana-Farber Cancer Institute
Kai W. Wucherpfennig: Dana-Farber Cancer Institute
Jun Qi: Harvard Medical School
Myles Brown: Dana-Farber Cancer Institute
Piotr Sicinski: Dana-Farber Cancer Institute
Thomas O. McDonald: Dana-Farber Cancer Institute
David Pellman: Dana-Farber Cancer Institute
Franziska Michor: Dana-Farber Cancer Institute
Kornelia Polyak: Dana-Farber Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16170-3

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