Mechanisms of Resistance to CDK4/6 Inhibitors in Hormone Receptor-Positive (HR  +) Breast Cancer: Spotlight on Convergent CDK6 Upregulation and Immune Signaling

AbstractPurpose of ReviewCDK4/6 inhibition (CDK4/6i) is a key component of first-line combination treatment with endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer (HR  + /HER2 − MBC). Understanding and overcoming resistance are ongoing areas of investigation. Diverse resistance mechanisms have been uncovered in cell cycle regulators and growth factor signaling components, converging on upregulation of CDK6 or on perturbation of the cell cycle downstream of CDK4/6. In this review, we discuss studies in the past few years that add new findings to this growing knowledge base.Recent FindingsRecent work has shown that CDK6 upregulation in breast cancer cells induces INK4 family members (p18INK4C and p15INK4B), which render CDK6 (but not CDK4) resistant to CDK4/6i. CDK6 can also form a CDK4/6i-resistant complex with p27KIP1 and (unlike CDK4) can sequester p21CIP1/WAF1 away from inhibiting CDK2 in the presence of CDK4/6i. These resistant complexes may be targetable by next-generation CDK4/6i such as proteolysis targeting chimeras (PROTACs). Separately, recent work has suggested that IFN-STAT1 signaling, especially over extended durations, may be a mediator of resistance rather than efficacy of CDK4/6i in breast cancer. This is based on descriptive analyses, and experiments are required to test this hypothesis.SummaryRecent research has revealed new mechanisms of CDK4/6i resistance in HR  + MBC, including CDK6 complexes with INK4 an...
Source: Current Breast Cancer Reports - Category: Cancer & Oncology Source Type: research