Targeted radiosensitization by the Chk1 inhibitor SAR-020106

Int J Radiat Oncol Biol Phys. 2013 Mar 15;85(4):1110-8. doi: 10.1016/j.ijrobp.2012.08.006. Epub 2012 Sep 14.

Abstract

Purpose: To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation.

Methods and materials: Colony and mechanistic in vitro assays and a xenograft in vivo model.

Results: SAR-020106 suppressed-radiation-induced G2/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G1 arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model.

Conclusion: The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle / radiation effects
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinase Inhibitor p21 / deficiency
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • DNA Repair / drug effects*
  • DNA Repair / genetics
  • DNA Repair / radiation effects*
  • G2 Phase / drug effects*
  • G2 Phase / genetics
  • HeLa Cells
  • Histones / analysis
  • Humans
  • Immunohistochemistry / methods
  • Isoquinolines / pharmacology*
  • Mice
  • Mice, Nude
  • Microscopy / methods
  • Mitosis / drug effects
  • Mitosis / radiation effects
  • Papillomaviridae / classification
  • Protein Kinases / drug effects*
  • Pyrazines / pharmacology*
  • Radiation Tolerance / drug effects*
  • Radiation Tolerance / genetics
  • Radiation Tolerance / radiation effects*
  • Radiation-Sensitizing Agents / pharmacology*
  • Time-Lapse Imaging / methods
  • Tumor Stem Cell Assay / methods
  • Tumor Suppressor Protein p53 / deficiency

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • H2AX protein, human
  • Histones
  • Isoquinolines
  • Pyrazines
  • Radiation-Sensitizing Agents
  • SAR 020106
  • Tumor Suppressor Protein p53
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse