Pharmacy and Pharmaceutical Sciences Commons^™

Therapeutic Challenge With A Cdk 4/6 Inhibitor Induces An Rb-Dependent Smac-Mediated Apoptotic Response In Non-Small Cell Lung Cancer., Thangavel Chellappagounder, Boopathi Ettickan, Yi Liu, Christopher Mcnair, Alex Haber, Maryna Perepelyuk, Anshul Bhardwaj, Sankar Addya, Adam Ertel, Sunday Shoyele, Ruth Birbe, Joseph M. Salvino, Adam P. Dicker, Karen E. Knudsen, Robert B. Den

Department of Radiation Oncology Faculty Papers

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.

Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results …