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.
Highlights
B romodomain and extra-terminal domain (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
To begin to characterize the response of TNBC cells, we first tested JQ1, palbociclib, and paclitaxel, alone and in combinations in vitro. We found that both JQ1 + palbociclib and JQ1 + paclitaxel inhibited growth of SUM159 cells significantly more than any of the three drugs alone (Fig. 1a)
Palbociclib was strongly synergistic in two TNBC lines, SUM159 and SUM149, and even more so in their JQ1-resistant derivatives, SUM159R and SUM149R (Fig. 1b)
Summary
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. 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. Several small molecule inhibitors have been developed, including the prototypical JQ1, iBET151, and OTX015, that block the binding of BET proteins to acetylated histones, thereby inhibiting the expression of these oncogenes and subsequently cell proliferation[7,8,9,10]. Cells can rapidly develop resistance to these drugs via multiple mechanisms, including bromodomainindependent chromatin binding of BRD4 through MED1 in TNBC11 and transcriptional activation via β-catenin in acute myeloid leukemia[13,14]. Effective combination therapies must be explored that can extend the efficacy of BET inhibitors and prevent or delay resistance
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