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Cancer Res. 2014 Dec 15;74(24):7430-41. doi: 10.1158/0008-5472.CAN-14-1439. Epub 2014 Oct 22.

Oncogenic KRAS confers chemoresistance by upregulating NRF2.

Author information

1
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona.
2
Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, Arizona.
3
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona. dzhang@pharmacy.arizona.edu.

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.

PMID:
25339352
PMCID:
PMC4268230
DOI:
10.1158/0008-5472.CAN-14-1439
[Indexed for MEDLINE]
Free PMC Article

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