Oncogenic KRAS confers chemoresistance by upregulating NRF2

Shasha Tao, Shue Wang, Seyed Javad Moghaddam, Aikseng Ooi, Eli Chapman, Pak Kin Wong, Donna Zhang

Research output: Contribution to journalArticle

104 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7430-7441
Number of pages12
JournalCancer Research
Volume74
Issue number24
DOIs
StatePublished - Dec 15 2014

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Drug Resistance
Non-Small Cell Lung Carcinoma
Cisplatin
Mutation
Nucleic Acid Regulatory Sequences
Response Elements
RNA Interference
Tumor Burden
Genes
Exons
Lung Neoplasms
Lung
Neoplasms
Ectopic Gene Expression
brusatol

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Oncogenic KRAS confers chemoresistance by upregulating NRF2. / Tao, Shasha; Wang, Shue; Moghaddam, Seyed Javad; Ooi, Aikseng; Chapman, Eli; Wong, Pak Kin; Zhang, Donna.

In: Cancer Research, Vol. 74, No. 24, 15.12.2014, p. 7430-7441.

Research output: Contribution to journalArticle

Tao, Shasha ; Wang, Shue ; Moghaddam, Seyed Javad ; Ooi, Aikseng ; Chapman, Eli ; Wong, Pak Kin ; Zhang, Donna. / Oncogenic KRAS confers chemoresistance by upregulating NRF2. In: Cancer Research. 2014 ; Vol. 74, No. 24. pp. 7430-7441.
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