Cytoplasmic, but not nuclear Nrf2 expression, is associated with inferior survival and relapse rate and response to platinum‐based chemotherapy in non‐small cell lung cancer

BACKGROUND: Several studies have previously indicated that nuclear factor erythroid 2‐related factor 2 (Nrf2) expression may promote tumor progression when the Keap1/Nrf2 pathway is activated, but few reports have demonstrated the role of cytoplasmic Nrf2 on tumorigenesis. METHODS: Immunohistochemistry was conducted to evaluate Nrf2 expression in 167 tumors from surgically‐resected patients with non‐small cell lung cancer (NSCLC). Univariate and multivariate analyses were performed to examine the association of Nrf2 expression with patients' prognosis. This study was conducted to examine the association of Nrf2 expression with tumor response to cisplatin‐based chemotherapy. RESULTS: Among these tumors, 56 and 32 of 167 tumors expressed Nrf2 in the cytoplasm (34% for C+/N‐) and in the cytoplasm/nucleus (19% for C+/N+), but not in the nucleus of tumor cells. Nrf2 was negatively expressed in the remainder of the tumor samples (C‐/N‐, 79 of 167, 47%). Univariate analysis indicated that patients with Nrf2 positive tumors (C+/N‐ plus C+/N+) had worse overall survival (OS), but not relapse‐free survival (RFS) than with Nrf2 negative tumors (C‐/N‐). However, patients with C+/N‐ tumors possessed worse OS and RFS than those with Nrf2 negative tumors (C‐/N‐). Multivariate analysis further confirmed the prognostic significance of patients with Nrf2 positive and C+/N‐ tumors on OS and RFS, but not on RFS for patients with Nrf2 positive tumors. Patients with Nrf2 positive and C+/N‐ tumors were determined to more frequently have an unfavorable response to cisplatin‐based chemotherapy than those with Nrf2 negative tumors. CONCLUSIONS: Cytoplasmic Nrf2 expression might potentially be used to predict poor prognosis and unfavorable response to cisplatin‐based chemotherapy in patients with NSCLC. KEY POINTS: The expression of cytoplasmic Nrf2 showed a significant relationship with patients' response to cisplatin‐based chemotherapy and influenced NSCLC prognosis. A proteasomal inhibitor such as carfilzomib might be used to improve the outcomes and therapeutic response to cisplatin‐based chemotherapy in patients with tumors showing cytoplasmic Nrf2 expression.