DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer

Catherine R. Sears, Sean A. Cooney, Helen Chin-Sinex, Marc S. Mendonca, John J. Turchi

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24 h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism.

Original languageEnglish (US)
Pages (from-to)35-46
Number of pages12
JournalDNA Repair
Volume40
DOIs
StatePublished - Apr 1 2016

Keywords

  • ATM
  • ATR
  • Cisplatin
  • Damage response
  • Lung cancer
  • Radiation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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