Open AccessA hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas
Author(s) -
Djihad Hadjadj,
Su-Jung Kim,
Thomas Denecker,
Laura Ben Driss,
JeanCharles Cadoret,
Chrystelle Maric,
Giuseppe Baldacci,
Fabien Fauchereau
Publication year - 2017
Publication title -
aging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 90
ISSN - 1945-4589
DOI - 10.18632/aging.101356
Subject(s) - palbociclib , cyclin dependent kinase 6 , wnt signaling pathway , cancer research , adrenocortical carcinoma , cyclin d1 , gsk 3 , biology , cyclin dependent kinase 4 , cancer , cyclin dependent kinase , medicine , cell cycle , endocrinology , kinase , cyclin dependent kinase 2 , signal transduction , microbiology and biotechnology , breast cancer , metastatic breast cancer
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/β-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 β-catenin). Together these results indicate that high CDK6 expression is found in aggressive tumors with activated Wnt/β-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 3β (GSK3β) responsible for the reduced amount of active β-catenin, and altered the amount of AXIN2 mRNA. Taken together, these data underline the impact of CDK4 and CDK6 inhibitors in treating adrenocortical carcinomas.