The non-kinase function of CDK6 is a key driver of acquired resistance to CDK4/6 inhibitors in Estrogen Receptor-positive breast cancer

The therapeutic efficacy of CDK4/6 inhibitors in ER+ breast cancer (BC) patients is presumed to arise from inhibition of the kinase function of CDK4 and 6 proteins. Despite their initial efficacy, development of acquired resistance to CDK4/6 inhibitors in metastatic ER+ BC patients is nearly universal, commonly through compensatory overexpression of CDK6. Here, we show that primary ER+ tumors show high CDK4 but very low to undetectable expression of CDK6, which suggests that the therapeutic efficacy of CDK4/6 inhibitors in ER+ BC patients is largely driven by inhibition of CDK4, rather than CDK6. Furthermore, we show that overexpression of CDK6 confers acquired resistance to CDK4/6 inhibitors, largely, through a kinase-independent function. Our findings challenge the dogma that CDK4/6-mediated phosphorylation of retinoblastoma protein (pRB) is necessary to ER+ BC cells to progress from G1 to S phase of cell cycle. Consequently, by taking advantage of the non-kinase function of CDK6, ER+ BC cells acquire independence from the kinase function of CDK4 and 6 for cell cycle progression. These findings highlight the limitations of the current standard-of-care treatments, which focus on merely inhibiting the kinase function of CDK4 and 6, and uncover the non-kinase function of CDK6 as a new targetable vulnerability to overcome acquired resistance to CDK4/6 inhibitors in ER+ BC.