NRF2 Mutation Confers Malignant Potential and Resistance to Chemoradiation Therapy in Advanced Esophageal Squamous Cancer

• DOI: 10.1593/neo.11750
• Publication Date: 2015-04-23T13:04:52Z
• Authors: Tatsuhiro Shibata; Akiko Kokubu; Shigeru Saito; Mako Narisawa-Saito; Hiroki Sasaki; Kazuhiko Aoyagi; Yuki Yoshimatsu; Yuji Tachimori; Ryoji Kushima; Tohru Kiyono; Masayuki Yamamoto
• Keywords: Targeted Therapy

Esophageal squamous cancer (ESC) is one of the most aggressive tumors gastrointestinal tract. A combination chemotherapy and radiation therapy (CRT) has improved clinical outcome, but molecular background determining effectiveness remains unknown. NRF2 a master transcriptional regulator stress adaptation, gain of-function mutation in confers resistance to stressors including anticancer therapy. Direct resequencing analysis revealed that Nrf2 gain-of-function occurred recurrently (18/82, 22%) advanced ESC cell lines (3/10). The presence was associated with tumor recurrence poor prognosis. Short hairpin RNA-mediated down-regulation cells harbor only mutated allele themutant conferred increased proliferation, attachment-independent survival, 5-fluorouracil γ-irradiation. Based on status, gene expression signatures were extracted from lines, their potential utility for monitoring prognosis examined cohort 33 pre-CRT cases ESC. significantly predictive prognostic CRT response. In conclusion, recurrent malignant ESC, resulting poorer outcome. Molecular can be applied as markers response CRT, efficient inhibition aberrant activation could promising approach CRT.