MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition

Abstract

// Marta Kovatcheva 1,5,* , David D. Liu 2,5,* , Mark A. Dickson 3,7 , Mary E. Klein 1,5 , Rachael O’Connor 8 , Fatima O. Wilder 8 , Nicholas D. Socci 6 , William D. Tap 3,7 , Gary K. Schwartz 7,9 , Samuel Singer 8 , Aimee M. Crago 5,8 and Andrew Koff 1,2,5 1 The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, USA 2 The Graduate Program in Biochemistry, Cellular and Molecular Biology, Weill College of Medicine, Cornell University, New York, USA 3 Department of Medicine, Weill College of Medicine, Cornell University, New York, USA 4 Department of Surgery, Weill College of Medicine, Cornell University, New York, USA 5 Program in Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, USA 6 Program in Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, USA 7 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA 8 Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA 9 Current address: Columbia University, New York, USA * These authors contributed equally to this work Correspondence to: Andrew Koff, email: // Aimee M. Crago, email: // Keywords : CDK4 inhibitors, MDM2, ATRX, senescence, geroconversion Received : December 03, 2014 Accepted : January 15, 2015 Published : January 31, 2015 Abstract CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy.