Role of KEAP1/NFE2L2 Mutations in the Chemotherapeutic Response of Patients with Non-Small Cell Lung Cancer.

Abstract

Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in <i>NFE2L2, KEAP1</i>, or <i>CUL3,</i> have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored. We investigated the effect of <i>Keap1</i> deletion on chemoresistance in cell lines from <i>Trp53</i>-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with <i>KEAP1, NFE2L2, or CUL3</i> mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups. Deletion of <i>Keap1</i> in <i>Trp53</i>-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the <i>KEAP1/NFE2L2/CUL3</i>-mutant cohort was 2.8 months compared with 8.3 months in the control group (<i>P</i> < 0.0001). Median overall survival (OS) was 11.2 months in the <i>KEAP1/NFE2L2/CUL3</i>-mutant group and 36.8 months in the control group (<i>P</i> = 0.006). <i>Keap1</i> deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in <i>KEAP1, NFE2L2</i>, or <i>CUL3</i> have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed.