p27kip1 expression and phosphorylation dictate Palbociclib sensitivity in KRAS-mutated colorectal cancer

Abstract In colorectal cancer, mutation of KRAS (RAS MUT ) reduces therapeutic options, negatively affecting prognosis of the patients. In this setting, administration of CDK4/6-inhibitors, alone or in combination with other drugs, is being tested as promising therapeutic strategy. Identifying sensitive patients and overcoming intrinsic and acquired resistance to CDK4/6 inhibition represent still open challenges, to obtain better clinical responses. Here, we investigated the role of the CDK inhibitor p27 kip1 in the response to the selective CDK4/6-inhibitor Palbociclib, in colorectal cancer. Our results show that p27 kip1 expression inversely correlated with Palbociclib response, both in vitro and in vivo. Generating a model of Palbociclib-resistant RAS MUT colorectal cancer cells, we observed an increased expression of p27 kip1 , cyclin D, CDK4 and CDK6, coupled with an increased association between p27 kip1 and CDK4. Furthermore, Palbociclib-resistant cells showed increased Src-mediated phosphorylation of p27 kip1 on tyrosine residues and low doses of Src inhibitors re-sensitized resistant cells to Palbociclib. Since p27 kip1 showed variable expression in RAS MUT colorectal cancer samples, our study supports the possibility that p27 kip1 could serve as biomarker to stratify patients who might benefit from CDK4/6 inhibition, alone or in combination with Src inhibitors.