Oncogenic KRAS confers chemoresistance by upregulating NRF2.

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.

• Authors: Shasha Tao, Shue Wang, Seyed Javad Moghaddam, Aikseng Ooi, Eli Chapman, Pak K Wong, Donna D Zhang
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 24 Pg. 7430-41 (Dec 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25339352 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• KRAS protein, human
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Proto-Oncogene Proteins
• Quassins
• brusatol
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• Cisplatin

Topics

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