LAUSR

Purpose of Review Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2−) metastatic breast cancer (MBC). However, optimal therapy after CDK4/6 inhibitors is unknown. This review provides an update on recent understanding of potential resistance mechanisms to CDK4/6 inhibitors and therapeutic strategies. Recent Findings CDK4/6 inhibitors are broadly effective for HR+/HER2− MBC. However, intrinsic and acquired resistance is inevitable. Although there are no established clinical predictors of response aside from ER positivity, several cell cycle-specific and non-specific mechanisms have emerged as potential resistance biomarkers and therapeutic targets in recent studies. Examples include loss of function mutations in RB1 or FAT1 , overexpression or amplification of CDK6 and CCNE1 , alterations of FGFR , and PI3K/mTOR-mediated CDK2 activation. Summary Biomarker studies and clinical trials targeting CDK4/6 inhibitor resistance are critical to improve treatments for HR+/HER2− MBC.