Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells

Abstract Palbociclibis a specific inhibitor of CDK4/6 and has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer. TCGA database reported that about half of gastric cancers exhibit abnormalities in cell-cycle-related molecules, suggesting that gastric cancer is a good candidate for palbociclibtreatment; however, the antitumor effects and predictive markersof palbociclibin gastric cancer remain incompletely described. Herein, the effect and predictive markersof palbociclibon gastric cancer cells were investigated. Our results reveal that palbociclibshowed anti-proliferative effects by inducing G1 phasecell-cycle arrest and cellular senescencein some gastric cancer cells. Basal protein expression level of cyclin Eshowed an inverse correlation of cancer cell sensitivity to palbociclib. In addition, palbociclibenhanced the antitumor effect of 5-FU in vitro and in vivo by modulating thymidine synthase expression. These results suggest that cyclin Eprotein expression determines the anti-proliferative effect of palbociclib, and palbociclibacts synergistically with 5-FU in gastric cancer. These findings provide a rationale for future clinical trials of palbocicliband 5-FU combination-based chemotherapy in gastric cancer.