Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

Approximately 80% of breast cancers overexpress the kinase BRK/PTK6, which has various oncogenic roles in breast cancer cell proliferation, survival and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we employed a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast cancer cell proliferation in vitro and in vivo. Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast cancer.