Shaping CDK4/6 Inhibitor Resistance: BRCA2 Germline Alterations Bias toward RB1 Inactivation

: The emergence of resistance to CDK4/6 inhibitors (CDK4/6i) is a major barrier to long-term survival in metastatic hormone receptor-positive (HR+) breast cancer. Mechanisms of CDK4/6i resistance are highly diverse and are currently unpredictable. In a recent issue of Nature, Safonov, Lee, and colleagues report that germline BRCA2 (gBRCA2) alterations predispose tumors toward loss-of-function alterations in RB1, a key mechanism of tumor escape from CDK4/6i. Leveraging large-scale clinical genomics, the authors show that gBRCA2-altered tumors are enriched for RB1 alterations and derive less benefit from CDK4/6i-based therapy, while retaining sensitivity to PARP inhibition. Mechanistically, they demonstrate that the shared location of BRCA2 and RB1 on chromosome 13q leads to RB1 hemizygosity in gBRCA2 tumors, and that homologous recombination deficiency-associated mutagenesis facilitates acquisition of a second inactivating hit. Furthermore, baseline RB1 hemizygosity predicts inferior outcomes on CDK4/6i independent of germline status, supporting its role as a predictive biomarker. These findings have immediate clinical implications regarding the sequencing of PARPi and CDK4/6i in patients with gBRCA2 mutations and highlight a potential opportunity to anticipate and intercept resistance, leading to more durable clinical benefit.