CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective

Abstract

CDK4/6 inhibitors have become game-changers in the treatment of estrogen receptor-positive (ER+) breast cancer, and in combination with endocrine therapy are the standard of care first-line treatment for ER+/HER2-negative advanced breast cancer. Although CDK4/6 inhibitors prolong survival for these patients, resistance is inevitable and there is currently no clear standard next-line treatment. There is an urgent unmet need to dissect the mechanisms which drive intrinsic and acquired resistance to CDK4/6 inhibitors and endocrine therapy to guide the subsequent therapeutic decisions. We will review the insights gained from preclinical studies and clinical cohorts into the diverse mechanisms of CDK4/6 inhibitor action and resistance, and highlight potential therapeutic strategies in the context of CDK4/6 inhibitor resistance.

Keywords: CDK4/6 inhibitor; breast cancer; endocrine therapy; estrogen receptor; resistance.

FIGURE 1

(A) The recently proposed mechanisms by which clinical CDK4/6 inhibitors act to block the cell cycle progression to DNA synthesis S phase and G₂ phase but cannot inhibit tyrosine kinase phosphorylated p27-CDK4/6-CycD complexes in ER + breast cancer (Guiley et al., 2019; Hafner et al., 2019; Schade et al., 2019; Pack et al., 2021). Non-cell cycle effects of CDK4/6 inhibition include reversible senescence (Thangavel et al., 2011; Torres-Guzman et al., 2017; Vijayaraghavan et al., 2017; Marinelli et al., 2020; Maskey et al., 2021; Mayayo-Peralta et al., 2021) and enhanced tumor immunogenicity (Goel et al., 2017; Peuker et al., 2022) (B) The mechanisms of ET and CDK4/6 inhibitor resistance currently reported in literature are highlighted. Black arrow shows pathway induction; red line shows pathway inhibition; dotted line indicates lower relative inhibition activity; P, phosphorylation. Images created with BioRender.com.