Well differentiated/dedifferentiated liposarcoma (WD/DDLS) is the most common form of soft tissue sarcoma, characterized by genomic amplification of the CDK4 and MDM2 oncogenes. This disease is both chemo- and radio- resistant, leaving surgical resection as the only treatment option. Recently, the CDK4 inhibitor (CDK4i) drug Palbociclib completed a Phase II clinical trial for WD/DDLS at MSKCC; the drug has received Breakthrough Designation from the FDA for its success in breast cancer. While 2/3 of WD/DDLS patients benefited from the drug, the remainder progressed while receiving therapy. Using a panel of patient-derived WD/DDLS cell lines, we found that all cells undergo growth arrest in response to Palbociclib, but only a subset of cells undergo senescence. Senescence was associated with decreases in MDM2 protein levels but was independent of INK4A and p53. Senescence suppression was dependent on the E3 ligase activity of MDM2. Triggering reactivation of senescence is considered a viable therapeutic option. Analysis of pre- and post-Palbociclib treatment patient biopsies revealed that down-regulation of MDM2 was associated with a favorable clinical outcome. Thus, we propose that there exist intrinsic mechanisms of resistance to CDK4i that determine whether MDM2 levels will change and senescence will be induced. We propose to use proteomic and genomic approaches to understand mechanisms of intrinsic and acquired resistance to CDK4i. Specifically, we will investigate the mechanism of MDM2-depnendent senescence induction, the novel substrate MDM2 ubiquitinates in order to suppress senescence and acquired mutations that promote senescence escape. Based on our preliminary data and a second, larger scale Phase II trial beginning enrollment at MSKCC, we have great promise to improve therapeutic modalities for these and future patient. We hope to identify novel therapeutic avenues that will increase the number of patients with favorable outcomes in response to Pablociclib, and provide secondary therapies once the inevitable resistance is acquired.