Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells.
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.
Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Elisa
E
Caiola
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Daniela
D
Salles
Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Roberta
R
Frapolli
Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Monica
M
Lupi
Department of Environmental Health Sciences, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Giuseppe
G
Rotella
Centro Nazionale Informazione Tossicologiche, Fondazione Salvatore Maugeri I.R.C.C.S., Pavia, Italy.
Anna
A
Ronchi
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Marina Chiara
MC
Garassino
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Nikola
N
Mattschas
Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Stefano
S
Colavecchio
Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Massimo
M
Broggini
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
Lisa
L
Wiesmüller
Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
Mirko
M
Marabese
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D000079923:Copper Transporter 1; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009154:Mutation; D041681:NIH 3T3 Cells; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C117307:KRAS protein, human; C490079:SLC31A1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin
KRAS; NSCLC; base excision repair; cisplatin; resistance