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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Oncogenic KRAS confers chemoresistance by upregulating NRF2.

Authors: Tao, Shasha; Wang, Shue; Moghaddam, Seyed Javad; Ooi, Aikseng; Chapman, Eli; Wong, Pak K; Zhang, Donna D

Published In Cancer Res, (2014 Dec 15)

Abstract: Oncogenic KRAS mutations found in 20% to 30% of all non-small cell lung cancers (NSCLC) are associated with chemoresistance and poor prognosis. Here we demonstrate that activation of the cell protective stress response gene NRF2 by KRAS is responsible for its ability to promote drug resistance. RNAi-mediated silencing of NRF2 was sufficient to reverse resistance to cisplatin elicited by ectopic expression of oncogenic KRAS in NSCLC cells. Mechanistically, KRAS increased NRF2 gene transcription through a TPA response element (TRE) located in a regulatory region in exon 1 of NRF2. In a mouse model of mutant KrasG12D-induced lung cancer, we found that suppressing the NRF2 pathway with the chemical inhibitor brusatol enhanced the antitumor efficacy of cisplatin. Cotreatment reduced tumor burden and improved survival. Our findings illuminate the mechanistic details of KRAS-mediated drug resistance and provide a preclinical rationale to improve the management of lung tumors harboring KRAS mutations with NRF2 pathway inhibitors.

PubMed ID: 25339352 Exiting the NIEHS site

MeSH Terms: Animals; Carcinoma, Non-Small-Cell Lung/genetics*; Carcinoma, Non-Small-Cell Lung/pathology; Cisplatin/administration & dosage; Drug Resistance/drug effects; Drug Resistance/genetics*; Gene Expression Regulation, Neoplastic/drug effects; Gene Silencing; Humans; Mice; Mutation; NF-E2-Related Factor 2/biosynthesis*; NF-E2-Related Factor 2/metabolism; Prognosis; Proto-Oncogene Proteins p21(ras); Proto-Oncogene Proteins/genetics*; Quassins/administration & dosage; Response Elements/genetics; ras Proteins/genetics*

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