Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer Natalia J. Sumi Brent M. Kuenzi Claire E. Knezevic Lily L. Remsing Rix Uwe Rix 10.1021/acschembio.5b00368.s001 https://acs.figshare.com/articles/journal_contribution/Chemoproteomics_Reveals_Novel_Protein_and_Lipid_Kinase_Targets_of_Clinical_CDK4_6_Inhibitors_in_Lung_Cancer/2097025 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 in 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 and 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. 2015-12-18 00:00:00 3CD PIK PIP LEE casein kinase 2 3R autophagy lipid kinases Palbociclib PD ribociclib AKT cell lung carcinoma LUSQ NSCLC H 157 cells CDK palbociclib II 4K