CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma

Cancer Cell. 2020 Mar 16;37(3):340-353.e6. doi: 10.1016/j.ccell.2020.01.007. Epub 2020 Feb 27.

Abstract

Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperate with DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry, thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequential administration of CDK4/6 inhibitors after taxanes cooperates to prevent cellular proliferation in pancreatic ductal adenocarcinoma (PDAC) cells, patient-derived xenografts, and genetically engineered mice with Kras G12V and Cdkn2a-null mutations frequently observed in PDAC. This effect correlates with the repressive activity of CDK4/6 inhibitors on homologous recombination proteins required for the recovery from chromosomal damage. CDK4/6 inhibitors also prevent recovery from multiple DNA-damaging agents, suggesting broad applicability for their sequential administration after available chemotherapeutic agents.

Keywords: CDK4/6 inhibitors; cell cycle; chemotherapy; pancreatic adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / administration & dosage
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Repair / drug effects
  • Drug Administration Schedule
  • Homologous Recombination / drug effects
  • Humans
  • Mice, Nude
  • Mice, Transgenic
  • Mutation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Paclitaxel / administration & dosage
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Piperazines / administration & dosage
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Pyridines / administration & dosage
  • Xenograft Model Antitumor Assays

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • palbociclib
  • Paclitaxel