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

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.

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

“…Recurrent deletions (Figure 4A) included ATRX (10% deep; 20% shallow), NF1 (6% deep; 22% shallow), and CDKN2A (2% deep; 42% shallow). Given that ATRX may be required for response to CDK4 inhibitors (Kovatcheva et al, 2015) and 30% of DDLPS have ATRX deletions, ATRX alterations may represent an important correlative biomarker in future clinical trials of CDK4 inhibitors in DDLPS.…”

Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

“…Recent studies in other tumour types have shown that palbociclib can induce cellular senescence, [40][41][42][43] which is an irreversible cell cycle arrest. 16 In HCC cells, we observed a reversible cell cycle arrest in most of the cell lines.…”

Targeting CDK4 and CDK6: From Discovery to Therapy

“…In an intriguing study (80), palbociclib treatment of seven RB-positive liposarcoma cell lines, each with chromosome 12q14 amplification of linked CDK4 and MDM2, arrested in a G1 state within 48 hours of drug exposure. Three of the cell lines subsequently expressed several senescence biomarkers and failed to resume proliferation when palbociclib was withdrawn.…”