ABL Kinases Modulate EZH2 Phosphorylation and Signaling in Metastatic Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains a leading cause of cancer associated deaths in women owing to its highly metastatic potential and limited treatment options. Recent studies have shown that expression of proteins associated with epigenetic regulation of gene expression are associated with metastatic relapse, however targeting epigenetic regulatory proteins has not resulted in effective therapies for TNBC in the clinic. The ABL tyrosine kinases promote metastasis of breast cancer cells in mouse models. However, a role of ABL kinases in the regulation of epigenetic processes in solid tumor metastasis remains unexplored. Here we show that inactivation of ABL kinases in bone metastatic TNBC cells led to a significant enrichment in gene signatures associated with the PRC2 protein complex, revealing a functional link between ABL kinases and the PRC2 complex. ABL inactivation promotes EZH2-T487 phosphorylation through the regulation of a FAK-CDK1 signaling axis. We find that phosphorylated EZH2 T487 or a phosphomimic EZH2 T487D mutant exhibit increased binding to non-canonical binding partners of EZH2 including c-MYC and ZMYND8. Notably, we identify a therapeutic vulnerability in TNBC cells whereby combination treatment with ABL allosteric inhibitors and EZH2 inhibitors elicits a synergistic decrease in TNBC cell survival in vitro, and impairs TNBC metastasis, prolonging survival of tumor-bearing mice treated with the combination therapy. One Sentence SummaryABL Kinases indirectly impact EZH2 catalytic activity by blocking a signaling cascade that leads to changes in the phosphorylation, protein interactions, and function of the PRC2 catalytic component EZH2 in TNBC.