Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer

Several selective CDK4/6 inhibitors are in clinical trials for non-small cell lung cancer (NSCLC), Palbociclib (PD0332991) is included in the phase II/III Lung MAP trial for squamous cell lung carcinoma (LUSQ). We noted differential Cellular activity between palbociclib and the structurally related ribociclib (LEE011) in LUSQ cells. Applying an unbiased mass spectrometry-based chemoproteomics approach in H157 cells and primary tumor samples, we here report distinct proteome-wide target profiles of these two drug candidates m LUSQ which encompass novel protein and, for palbociclib only, lipid kinases. In addition to CDK4 and 6, we observed CDK9 as a potent target of both drugs Palbociclib interacted with Several kinases not targeted by ribociclib, such as casein kinase 2 end PIK3R4, which regulate autophagy. Furthermore, palbociclib engaged several lipid kinases, most notably, PIK3CD and PIP4K2A/B/C: Accordingly, we observed modulation of autophagy and inhibition Of AKT signaling by palbociclib but not ribociclib.