Antitumor Activity Of A Novel CDK4/6 Inhibitor,SHR6390,in RB Positive Tumors

Growth and proliferation of cell depend on the progression of the cell cycle.Dysregulation of cell cycle progression lead to uncontrolled cell proliferation,which plays an important role in the occurrence and development of cancer.The two most important proteins in cell cycle progression are cyclin and CDKs.The Cyclin D-CDK4/6-RB pathway controls the cell cycle progression through regulating the G1/S check point,and the dysregulation of the cyclin D-CDK4/6-RB pathway results in increased proliferation,which frequently observed in many types of cancer.Therefore,inhibition of the cyclin-dependent kinase(CDK)4/6-retinoblastoma(RB)pathway is an effective therapeutic strategy against cancer.Here,we performed a preclinical investigation of the antitumor activity of SHR6390,a novel CDK4/6 inhibitor.In in vitro,we examined the effects of SHR6390 on inhibition of tumor cell growth through SRB or MTT.The effects of SHR6390 on protein expression of RB and cyclin D1 and the level of phosphorylated RB protein by western blotting.In in vivo,the growth of tumor after SHR6390 treatment was observed by xenograft tumor models.We found that SHR6390 exhibited potent antiproliferative activity against a wide range of human RB-positive tumor cells in vitro,and exclusively induced G1 arrest and cellular senescence,with a concomitant reduction in the levels of Ser780-phosphorylated RB protein.In vivo study showed that compared with the well-known CDK4/6 inhibitor,palbociclib,orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts,and produced marked tumor regression in some models,such as COLO 205 model,in association with sustained target inhibition in tumor tissues.Furthermore,SHR6390 overcame resistance to endocrine therapy and HER2-targeting antibody in ER-positive and HER2-positive breast cancer,respectively.Moreover,MCF7/ARO model,represents postmenopausal breast cancer in many respects,and MCF7 model indicated that SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER-positive breast cancer.Taken together,our findings indicate that SHR6390 possess potent efficacy in inhibition of RB positive tumor cells in vitro and in vivo as well as exert synergistic antitumor efficacy in RB positive breast cancer when combine with endocrine therapy.SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent and our research also contribute to ongoing clinical trials.