Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features.

Abstract

PURPOSE:

To understand the role of nuclear factor erythroid-2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in non-small cell lung cancer (NSCLC), we studied their expression in a large series of tumors with annotated clinicopathologic data, including response to platinum-based adjuvant chemotherapy.

EXPERIMENTAL DESIGN:

We determined the immunohistochemical expression of nuclear Nrf2 and cytoplasmic Keap1 in 304 NSCLCs and its association with patients' clinicopathologic characteristics, and in 89 tumors from patients who received neoadjuvant (n = 26) or adjuvant platinum-based chemotherapy (n = 63). We evaluated NFE2L2 and KEAP1 mutations in 31 tumor specimens.

RESULTS:

We detected nuclear Nrf2 expression in 26% of NSCLCs; it was significantly more common in squamous cell carcinomas (38%) than in adenocarcinomas (18%; P < 0.0001). Low or absent Keap1 expression was detected in 56% of NSCLCs; it was significantly more common in adenocarcinomas (62%) than in squamous cell carcinomas (46%; P = 0.0057). In NSCLC, mutations of NFE2L2 and KEAP1 were very uncommon (2 of 29 and 1 of 31 cases, respectively). In multivariate analysis, Nrf2 expression was associated with worse overall survival [P = 0.0139; hazard ratio (HR), 1.75] in NSCLC patients, and low or absent Keap1 expression was associated with worse overall survival (P = 0.0181; HR, 2.09) in squamous cell carcinoma. In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P = 0.0410; HR, 3.37).

CONCLUSIONS:

Increased expression of Nrf2 and decreased expression of Keap1 are common abnormalities in NSCLC and are associated with a poor outcome. Nuclear expression of Nrf2 in malignant lung cancer cells may play a role in resistance to platinum-based treatment in squamous cell carcinoma.

• Authors: Luisa M Solis, Carmen Behrens, Wenli Dong, Milind Suraokar, Natalie C Ozburn, Cesar A Moran, Alejandro H Corvalan, Shyam Biswal, Stephen G Swisher, B Nebiyou Bekele, John D Minna, David J Stewart, Ignacio I Wistuba
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 14 Pg. 3743-53 (Jul 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20534738 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2010 AACR.

Chemical References

• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Organoplatinum Compounds

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Nucleolus (metabolism)
• Chemotherapy, Adjuvant
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Kelch-Like ECH-Associated Protein 1
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mutation
• NF-E2-Related Factor 2 (biosynthesis, genetics)
• Organoplatinum Compounds (therapeutic use)
• Retrospective Studies
• Treatment Outcome