KRAS-NRF2 in Cisplatin Resistance

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. Cancer Res; 74(24); 7430–41. ©2014 AACR.
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Pathobiology Source Type: research

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Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
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Source: Journal of the American Society of Cytopathology - Category: Cytology Source Type: research
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Source: Journal of Oncology - Category: Cancer & Oncology Tags: J Oncol Source Type: research
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Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
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Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
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Source: The Annals of Thoracic Surgery - Category: Cardiovascular & Thoracic Surgery Source Type: research
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Source: The Annals of Thoracic Surgery - Category: Cardiovascular & Thoracic Surgery Source Type: research
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