Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells
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Elisa Caiola1, Daniela Salles2, Roberta Frapolli3, Monica Lupi3, Giuseppe Rotella4, Anna Ronchi5, Marina Chiara Garassino6, Nikola Mattschas2, Stefano Colavecchio1, Massimo Broggini1, Lisa Wiesmüller2, Mirko Marabese1
1Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
2Department of Obstetrics and Gynecology of the University of Ulm, Ulm, Germany
3Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
4Department of Environmental Health Sciences, IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
5Centro Nazionale Informazione Tossicologiche, Fondazione Salvatore Maugeri I.R.C.C.S., Pavia, Italy
6Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Massimo Broggini, e-mail: firstname.lastname@example.org
Keywords: KRAS, resistance, NSCLC, base excision repair, cisplatin
Received: July 21, 2015 Accepted: August 20, 2015 Published: September 02, 2015
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.
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