American Association for Cancer Research
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Figure S4 from Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2

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posted on 2023-03-30, 22:44 authored by Shasha Tao, Shue Wang, Seyed Javad Moghaddam, Aikseng Ooi, Eli Chapman, Pak K. Wong, Donna D. Zhang

Figure S4. Larger images of the IHC analyses shown in Figure 2B.

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ARTICLE 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. Cancer Res; 74(24); 7430–41. ©2014 AACR.