title: CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers.
abstract: Loss-of-function mutations in p16(INK4A) (CDKN2A) occur in approximately 80% of sporadic pancreatic ductal adenocarcinoma (PDAC), contributing to its early progression. Although this loss activates the cell-cycle-dependent kinases CDK4/6, which have been considered as drug targets for many years, p16(INK4A)-deficient PDAC cells are inherently resistant to CDK4/6 inhibitors. This study searched for targeted therapies that might synergize with CDK4/6 inhibition in this setting. We report that the IGF1R/IR inhibitor BMS-754807 cooperated with the CDK4/6 inhibitor PD-0332991 to strongly block proliferation of p16(INK4A)-deficient PDAC cells in vitro and in vivo. Sensitivity to this drug combination correlated with reduced activity of the master cell growth regulator mTORC1. Accordingly, replacing the IGF1R/IR inhibitor with the rapalog inhibitor temsirolimus broadened the sensitivity of PDAC cells to CDK4/6 inhibition. Our results establish targeted therapy combinations with robust cytostatic activity in p16(INK4A)-deficient PDAC cells and possible implications for improving treatment of a broad spectrum of human cancers characterized by p16(INK4A) loss.
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Heilmann
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Veronika
authors.initials: V
authors.lastname: Ecker
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Brandon N
authors.initials: BN
authors.lastname: Nicolay
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Authors' Affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts dyson@helix.mgh.harvard.edu.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D016160:Retinoblastoma Protein / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D017526:Receptor, IGF Type 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6