Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors.

摘要: Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy mitigated by uniformly low levels myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have clinically advanced cyclin-dependent kinase (CDK) effective MCL-1 patients, and, importantly, well tolerated. We, therefore, tested whether CDK dinaciclib, could block preclinical HER2-amplified cancer models therefore sensitize these cancers dual HER2/EGFR neratinib lapatinib, as novel selective inhibitor tucatinib. Indeed, we found dinaciclib suppresses RNA highly at both vitro vivo. This combination was tolerable Mechanistically, liberating effector BCL-2 protein, BAK, results robust apoptosis. Thus, may effectively combine with present chemotherapy-free therapeutic strategy cancer, which can immediately clinic.