Targeting CDK4/6 in breast cancer

Abstract

Dysregulation of the cell cycle machinery, particularly the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark of breast cancer pathogenesis. The introduction of CDK4/6 inhibitors has transformed the treatment landscape for hormone receptor-positive breast cancer by effectively targeting abnormal cell cycle progression. However, despite their initial clinical success, drug resistance remains a significant challenge, with no reliable biomarkers available to predict treatment response or guide strategies for managing resistant populations. Consequently, numerous studies have sought to investigate the mechanisms driving resistance to optimize the therapeutic use of CDK4/6 inhibitors and improve patient outcomes. Here we examine the molecular mechanisms regulating the cell cycle, current clinical applications of CDK4/6 inhibitors in breast cancer, and key mechanisms contributing to drug resistance. Furthermore, we discuss emerging predictive biomarkers and highlight potential directions for overcoming resistance and enhancing therapeutic efficacy.

Fig. 1. Resistance mechanisms to CDK4/6 inhibitors.

This schematic illustrates the key genetic and nongenetic mechanisms contributing to resistance against CDK4/6 inhibitors in HR⁺/HER2⁻ breast cancer. In the canonical pathway, mitogenic and hormone-signaling pathways activate the cyclin D–CDK4/6 complex, which phosphorylates Rb, effectively releasing E2F transcription factors and promoting cell cycle entry. LOF mutations in Rb represent the most well-documented primary resistance mechanism to CDK4/6 inhibitors. Another genetic mechanism involves FAT1 LOF mutations, which activate the Hippo pathway, leading to CDK6 overexpression and the formation of CDK6‒INK4 complexes resistant to CDK4/6 inhibitors. Mutations in mitogenic and hormone-signaling pathways, such as ERBB2, FGFR1-3, PIK3CA, NF1 and ESR1, which can increase c-Myc expression, are frequently observed in CDK4/6 inhibitor-resistant tumors. Nongenetic mechanisms include Rb degradation, bypassing CDK4/6 inhibition to alternatively enter the cell cycle. However, this noncanonical pathway for Rb inactivation is incomplete, necessitating E2F amplification by c-Myc, which has been shown to inversely correlate with the outcomes of CDK4/6 inhibitor therapies. The loss of AMBRA1 stabilizes cyclin D and enables its interaction with CDK2, driving resistance. In addition, amplification of AURKA and CCNE1/2 upregulates CDK2 activity, allowing tumor cells to bypass the dependency on CDK4/6. Alterations in specific miRNAs also contribute to CDK4/6 inhibitor resistance. This model emphasizes the multifaceted nature of resistance mechanisms, highlighting the roles of genetic mutations, signaling pathway alterations and transcriptional regulation.