CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers

Cancer Res. 2014 Jul 15;74(14):3947-58. doi: 10.1158/0008-5472.CAN-13-2923. Epub 2014 Jul 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cellular Senescence / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Gene Deletion
  • Humans
  • Mice
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Retinoblastoma Protein / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Retinoblastoma Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Receptor, IGF Type 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6