Therapeutic efficacy critically depends on intact CDK4/6-cyclin D-Rb signaling, with heightened sensitivity observed in tumors exhibiting pathway dependency—such as ER-positive breast cancers with cyclin D1 amplification and Rb-proficient colorectal carcinomas (Klein et al., 2018; Spring et al., 2020; Vasaikar et al., 2019). The gene discussed is RB1; the disease is colorectal carcinoma.