Although targeting PRMT5 is not synthetic lethal to RB-deficiency, its mechanism of cell cycle inhibition provides a rationale for future studies testing first-generation PRMT5i also in RB-competent, CDK4/6i-refractory breast cancers with other mechanisms of resistance (e.g., CCNE1 overexpression, FAT1 loss, PTEN loss, etc.)9,12,56,57. Here, CDK4 is linked to breast cancer.