Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK46 Inhibition

Abstract EN

Triple positive breast cancers overexpress both the human epidermal growth factor receptor 2 (HER2) oncogene and the hormonal receptors (HR) to estrogen and progesterone.

These cancers represent a unique therapeutic challenge because of a bidirectional cross-talk between the estrogen receptor alpha (ERα) and HER2 pathways leading to tumor progression and resistance to targeted therapy.

Attempts to combine standard of care HER2-targeted drugs with antihormonal agents for the treatment of HR+/HER2+ breast cancer yielded encouraging results in preclinical experiments but did improve overall survival in clinical trial.

In this review, we dissect multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarize prior clinical trials of targeted agents, and describe novel rational drug combinations that include antihormonal agents, HER2-targeted drugs, and CDK4/6 inhibitors for treatment of the HR+/HER2+ breast cancer subtype.