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

High proliferation rate and mutation density are usually indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas as well as the expression levels of 136 genes associated with DNA metabolic process G1/S phase transition. In 79 samples downloaded within the Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most crucial link with shorter time to relapse and poorer survival of patients. A hierarchical clustering approach come up with most tumors wealthy in levels of CDK6 mRNA into one group. These tumors possess a inclination to cumulate mutations activating the Wnt/ß-catenin path and show reduced MIR506 expression. Really, the quantity of MIR506 RNA is inversely correlated while using levels of both CDK6 and CTNNB1 (encoding ß-catenin). Together these results indicate topping CDK6 expression are available in aggressive tumors with activated Wnt/ß-catenin path. Thus we tested the end result 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 caused senescence in SW-13 cells, only palbociclib was effective round the retinoblastoma protein (pRB)-negative NCI-H295R cells, by inducing apoptosis. In NCI-H295R cells, palbociclib caused an increase in the active kind of Glycogen Synthase Kinase 3ß (GSK3ß) responsible for the minimal quantity of active ß-catenin, and altered the amount of AXIN2 mRNA. Taken together, these data underline the end result of CDK4 and CDK6 inhibitors for adrenocortical Ribociclib carcinomas.