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/ß-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 ß-catenin). Together these results indicate that high CDK6 expression is found in aggressive tumors with activated Wnt/ß-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 3ß (GSK3ß) responsible for the reduced amount of active ß-catenin, and altered the amount of AXIN2 mRNA. Taken together, these data underline the impact of CDK4 and CDK6 inhibitors in treating adrenocortical carcinomas.