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

• Published in: Clinical cancer research 2020-01, Vol.26 (1), p.274-281
• Main Authors: Jeong, Youngtae, Hellyer, Jessica A, Stehr, Henning, Hoang, Ngoc T, Niu, Xiaomin, Das, Millie, Padda, Sukhmani K, Ramchandran, Kavitha, Neal, Joel W, Wakelee, Heather, Diehn, Maximilian
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carboplatin - administration & dosage; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cisplatin - administration & dosage; Drug Resistance, Neoplasm - genetics; Etoposide - administration & dosage; Female; Humans; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Neoplasm Staging; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Paclitaxel - administration & dosage; Prognosis; Spheroids, Cellular; Survival Rate
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1237

Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in , or 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 deletion on chemoresistance in cell lines from -based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with 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 in -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 -mutant cohort was 2.8 months compared with 8.3 months in the control group ( < 0.0001). Median overall survival (OS) was 11.2 months in the -mutant group and 36.8 months in the control group ( = 0.006). deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in , or 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.