A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas.

ABSTRACT: High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas and the expression levels of 136 genes involved in DNA metabolism and G1/S phase transition. In 79 samples downloaded from The Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most significant association with shorter time to relapse and poorer survival of patients. A hierarchical clustering approach assembled most tumors with high levels of CDK6 mRNA into one group. These tumors tend to cumulate mutations activating the Wnt/?-catenin pathway and show reduced MIR506 expression. Actually, the level of MIR506 RNA is inversely correlated with the levels of both CDK6 and CTNNB1 (encoding ?-catenin). Together these results indicate that high CDK6 expression is found in aggressive tumors with activated Wnt/?-catenin pathway. Thus we tested the impact of Food and Drug Administration-approved CDK4 and CDK6 inhibitors, namely palbociclib and ribociclib, on SW-13 and NCI-H295R cells. While both drugs reduced viability and induced senescence in SW-13 cells, only palbociclib was effective on the retinoblastoma protein (pRB)-negative NCI-H295R cells, by inducing apoptosis. In NCI-H295R cells, palbociclib induced an increase of the active form of Glycogen Synthase Kinase 3? (GSK3?) responsible for the reduced amount of active ?-catenin, and altered the amount of AXIN2 mRNA. Taken together, these data underline the impact of CDK4 and CDK6 inhibitors in treating adrenocortical carcinomas.

SUBMITTER: Hadjadj D 

PROVIDER: S-EPMC5764399 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature