title: Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer.
abstract: 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.
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612-9497, United States.|Cancer Biology Ph.D. Program, University of South Florida , Tampa, Florida 33620, United States.
authors.forename: Natalia J
authors.initials: NJ
authors.lastname: Sumi
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612-9497, United States.|Cancer Biology Ph.D. Program, University of South Florida , Tampa, Florida 33620, United States.
authors.forename: Brent M
authors.initials: BM
authors.lastname: Kuenzi
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612-9497, United States.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Knezevic
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612-9497, United States.
authors.forename: Lily L
authors.initials: LL
authors.lastname: Remsing Rix
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612-9497, United States.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D016503:Drug Delivery Systems; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D040901:Proteomics; D011687:Purines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib; C000589651:ribociclib