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A large scale proteome analysis of the gefitinib primary resistance overcome by KDAC inhibition in KRAS mutated adenocarcinoma cells overexpressing amphiregulin

Abstract : KDAC inhibitors (KDACi) overcome gefitinib primary resistance in non-small cell lung cancer (NSCLC) including mutant-KRAS lung adenocarcinoma. To identify which proteins are involved in the restoration of this sensitivity and to provide new therapeutic targets for mutant-KRAS lung adenocarcinoma, we performed an iTRAQ quantitative proteomic analysis after subcellular fractionation of H358-NSCLC treated with gefitinib and KDACi (TSA/NAM) versus gefitinib alone. The 86 proteins found to have been significantly dysregulated between the two conditions, were mainly involved in cellular metabolism and cell transcription processes. As expected, the pathway related to histone modifications was affected by the KDACi. Pathways known for controlling tumor development and (chemo)-resistance (miRNA biogenesis/glutathione metabolism) were affected by the KDACi/gefitinib treatment. Moreover, 57 dysregulated proteins were upstream of apoptosis (such as eEF1A2 and STAT1) and hence provide potential therapeutic targets. The inhibition by siRNA of eEF1A2 expression resulted in a slight decrease in H358-NSCLC viability. In addition, eEF1A2 and STAT1 siRNA transfections suggested that both STAT1 and eEF1A2 prevent AKT phosphorylation known for enhancing gefitinib resistance in NSCLC. Therefore, altogether our data provide new insights into proteome regulations in the context of overcoming the NSCLC resistance to gefitinib through KDACi in H358 KRAS mutated and amphiregulin-overexpressing NSCLC cells.
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https://hal.univ-grenoble-alpes.fr/hal-01987911
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Soumis le : lundi 20 janvier 2020 - 11:25:26
Dernière modification le : mercredi 7 octobre 2020 - 13:10:12

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Sylvia Lehmann, Michel Seve, Laetitia Vanwonterghem, Sylvie Michelland, Valérie Cunin, et al.. A large scale proteome analysis of the gefitinib primary resistance overcome by KDAC inhibition in KRAS mutated adenocarcinoma cells overexpressing amphiregulin. Journal of Proteomics, Elsevier, 2019, 195, pp.114-124. ⟨10.1016/j.jprot.2019.01.009⟩. ⟨hal-01987911⟩

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