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.