TY - JOUR
T1 - Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells
AU - Caiola, Elisa
AU - Salles, Daniela
AU - Frapolli, Roberta
AU - Lupi, Monica
AU - Rotella, Giuseppe
AU - Ronchi, Anna
AU - Garassino, Marina Chiara
AU - Mattschas, Nikola
AU - Colavecchio, Stefano
AU - Broggini, Massimo
AU - Wiesmüller, Lisa
AU - Marabese, Mirko
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Base excision repair
KW - Cisplatin
KW - KRAS
KW - NSCLC
KW - Resistance
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U2 - 10.18632/oncotarget.5019
DO - 10.18632/oncotarget.5019
M3 - Article
AN - SCOPUS:84945116838
VL - 6
SP - 30072
EP - 30087
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 30
ER -