Study On The Value And Strategy Of CDK4/6 Inhibitors In Ovarian Cancer

Purpose: The CDK4/6 inhibitor,palbociclib,recently entered the clinic for breast cancer treatment.However,translating the efficacy of palbociclib to other solid tumors has been a challenge,especially for aggressive solid tumors.To figure out the application of palbociclib in ovarian cancer,we explored the efficacy and mechanism of palbociclib in multiple preclinical models of ovarian cancer and explored the combined strategy with palbociclib in ovarian cancer.Methods: We analyzed CDK4/6 expression and prognosis using The Cancer Genome Atlas(TCGA),Gene Expression Omnibus(GEO)and Genotype Tissue Expression(GTEx)data.Subsequently,we verified the effect of CDK4/6 on immunity in OC cell lines and animal models.Further,we tested the sensitivity of palbociclib in ovarian cancer multiple models,PDO,PDX,2D/3D cell lines,and used RPPA technology and RNA sequencing to identify the mechanism of palbociclib’s primary and acquired resistance.Finally,combination regimens were tested to overcome primary and acquired resistance to palbociclib in OC.Results: CDK4/6 expression was higher in OC tissues than in normal ovarian tissues,and the high expression levels of CDK4/6 contributed to the immunosuppressive state of OC and were thus related to the poor prognosis of OC patients.This was also in general agreement with the results of OC cell line and animal experiments.Mechanistically,the CDK4/6 inhibitor palbociclib increased the secretion of interferon(IFN)-γ and the interferon-stimulated gene(ISG)response,thereby upregulating the expression of antigenpresenting molecules;this effect was partly dependent on the STING pathway.Additionally,according to public data,the LRRC75A-AS1-hsa-mi R-330-5p axis might inhibit the immune response of OC patients by upregulating CDK4/6,leading to a poor prognosis.Furthermore,the effect of palbociclib as a single agent was limited because of the primary and acquired resistance in multiple OC models,2D/3D cell lines,PDX,and PDO models.Mechanically,activated MAPK/PI3K-AKT pathway and increased cell cycle-related proteins were associated with intrinsic and acquired palbociclib resistance in OC,which was overcome with the addition of AZD5153.Nonetheless,the cotreatment of AZD5153 and palbociclib more profoundly repressed cell proliferation and increased apoptosis.Conclusions: Although palbociclib activated the immune microenvironment of OC,the effect of palbociclib as a single agent was limited because of the primary and acquired resistance.However,cotreatment of AZD5153 and palbociclib worked well in multiple preclinical OC models.