The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo

Oncotarget. 2015 Dec 29;6(42):44289-305. doi: 10.18632/oncotarget.6247.

Abstract

ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.

Keywords: ATM and Rad-3-related (ATR); DNA damage response; ataxia telangiectasia mutated (ATM); cisplatin; non-small cell lung cancer (NSCLC).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins / deficiency*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Biological Availability
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cellular Senescence / drug effects
  • Cisplatin / administration & dosage*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice, Nude
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyrimidines / administration & dosage*
  • Pyrimidines / pharmacokinetics
  • RNA Interference
  • Sulfoxides / administration & dosage*
  • Sulfoxides / pharmacokinetics
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • AZD6738
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfoxides
  • Deoxycytidine
  • gemcitabine
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Cisplatin