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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3743-3753
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number14
DOIs
StatePublished - Jul 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Solis, L. M., Behrens, C., Dong, W., Suraokar, M., Ozburn, N. C., Moran, C. A., Corvalan, A. H., Biswal, S., Swisher, S. G., Bekele, B. N., Minna, J. D., Stewart, D. J., & Wistuba, I. I. (2010). Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clinical Cancer Research, 16(14), 3743-3753. https://doi.org/10.1158/1078-0432.CCR-09-3352