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• W2564419908 abstract "Background: KRAS is one of the best characterized genes in cancer but, despite great efforts made in the past three decades, it remains practically undruggable. KRAS is frequently mutated in the three first cancer leading cause of death in the western countries, which are lung, colorectal (CRC) and pancreatic cancers and has been associated to aggressive phenotypes and reduced response to treatment. Unlike in CRC, where mutated KRAS role seems defined, in non-small-cell lung cancer (NSCLC), which accounts for the 85% of all lung cancers, its role as predictive or prognostic factor has not been established yet and the only definition of KRAS status seems not to be sufficient to shed light on this open question. KRAS has been found mutated mostly at codon 12, in about 20% of NSCLCs and in smokers, but the result of this process is a pool of mutations differing for the replaced basis and for the percentage the substitutions have been observed in other types of cancer. In fact, while in CRC the most common KRAS mutation is the G12D, the G12C substitution is the most abundant in NSCLC. It has been assumed that different KRAS mutations in the same position could differently impact on drug response. We generated an isogenic system in NCI-H1299 cell line with KRAS most common mutations found in NSCLC patients (G12C, G12D and G12V) to test this hypothesis. The G12C clone resulted resistant in vitro and in vivo to cisplatin, which constitutes the standard first line regimen in NSCLC. Methods: The effect of cisplatin on signalling pathways and DNA damage response was determined by western blotting, immunofluorescence and Real-Time PCR. Platinum adducts on DNA were revealed by DRC-ICP-MS. Results: The MAPK and PI3K pathways modulation induced by cisplatin did not seem to account for the different cisplatin sensitivities observed among the clones. Factors involved in processes like cisplatin intracellular uptake and inactivation have been investigated, but the slight differences observed did not explain the behavior of clones treated with cisplatin. Even if cisplatin showed a similar ability to enter the cells and to reach the DNA, concordant results seemed to indicate that an increased removal of platinum bound to DNA might be responsible for the resistance of G12C clone. A reduced G2/M cell cycle phase block was observed in the G12C clone compared to all the others after cisplatin treatment. This observation was supported by a much faster reduction of the levels of platinum adducts on DNA in G12C cells and, at the same time, by a barely detectable H2AX activation following treatment. We hypothesized that a DNA repair mechanism, able to faster remove platinum from DNA before the formation of double strand cross-links, could be involved in the resistance of G12C clone. Preliminary experiments on Nucleotide Excision Repair and Fanconi Anemia repair mechanisms, which have been associated to the removal of adducts from DNA, excluded these systems as responsible for cisplatin resistance. Conclusions: Altogether these data reveal the possibility that KRAS mutations differently influence the response to cisplatin in NSCLC. Further studies are ongoing to address this point. Understanding the molecular factors involved in the different response of KRAS clones to cisplatin could be useful in the clinical setting to improve the limited efficacy on KRAS mutated NSCLC patients of this drug, which nevertheless still represents the best available therapy. Supported by CARIPLO (2010-0794) and AIRC (IG 12915). Citation Format: Elisa Caiola, Roberta Frapolli, Massimo Broggini, Marina Chiara Garassino, Gabriella Farina, Mirko Marabese. Studies on the molecular mechanisms responsible for cisplatin resistance associated to KRAS G12C mutation in NSCLC. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A54. doi: 10.1158/1557-3125.RASONC14-A54" @default.
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• W2564419908 date "2014-12-01" @default.
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• W2564419908 title "Abstract A54: Studies on the molecular mechanisms responsible for cisplatin resistance associated to KRAS G12C mutation in NSCLC" @default.
• W2564419908 doi "https://doi.org/10.1158/1557-3125.rasonc14-a54" @default.
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