Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells

Elisa Caiola, Daniela Salles, Roberta Frapolli, Monica Lupi, Giuseppe Rotella, Anna Ronchi, Marina Chiara Garassino, Nikola Mattschas, Stefano Colavecchio, Massimo Broggini, Lisa Wiesmüller, Mirko Marabese

Research output: Contribution to journalArticlepeer-review

Abstract

KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatments but this feature lacks a mechanistic basis so far. In tumors, KRAS was found to be mutated mostly at codons 12 and 13 and a pool of mutations differing in the base alteration and the amino acid substitution have been described. The different KRAS mutations may differently impact on cancerogenesis and drug sensitivity. On this basis, we hypothesized that a different KRAS mutational status in NSCLC patients determines a different profile in the tumor response to treatments. In this paper, isogenic NSCLC cell clones expressing mutated forms of KRAS were used to determine the response to cisplatin, the main drug used in the clinic against NSCLC. Cells expressing the KRAS(G12C) mutation were found to be less sensitive to treatment both in vitro and in vivo. Systematic analysis of drug uptake, DNA adduct formation and DNA damage responses implicated in cisplatin adducts removal revealed that the KRAS(G12C) mutation might be particular because it stimulates Base Excision Repair to rapidly remove platinum from DNA even before the formation of cross-links. The presented results suggest a different pattern of sensitivity/resistance to cisplatin depending on the KRAS mutational status and these data might provide proof of principle for further investigations on the role of the KRAS status as a predictor of NSCLC response.

Original languageEnglish
Pages (from-to)30072-30087
Number of pages16
JournalOncotarget
Volume6
Issue number30
DOIs
Publication statusPublished - 2015

Keywords

  • Base excision repair
  • Cisplatin
  • KRAS
  • NSCLC
  • Resistance

ASJC Scopus subject areas

  • Oncology

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