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

Abstract

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

Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1

“…There are somatic mutations in the KEAP1 and NRF2 genes in various human cancer cells that cause constitutive NRF2 activation and promote cancer malignancy (19)(20)(21)(22). Notably, all of the somatic mutations in the NRF2 gene reside within or near the sequence encoding the DLG and ETGE motifs and introduce substitution mutations of amino acid residues.…”

“…These mutations impair two-site recognition between the KEAP1 homodimer and the Neh2 domain of NRF2 (19), resulting in the constitutive activation or derepression of NRF2. NRF2 protects cancer cells against stress from the microenvironment or anticancer drugs and confers radiation resistance on cancer cells (20)(21)(22). Indeed, patients with somatic mutations in NRF2 or KEAP1 have a poor prognosis (19,(22)(23)(24)(25).…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…Mutations also occur more frequently in Nrf2 than in Keap1. Mutations in the ETGE and DLG motifs impair two-site substrate recognition of Keap1, which leads to the stabilisation of Nrf2 and, subsequently, activation of target genes of Nrf2 (Shibata et al 2011;Kim et al 2010a, b). Somatic mutations in CUL3 were identified in hereditary type 2 papillary renal cell carcinoma (Ooi et al 2013).…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…HNSC-G1 patients showed very poor survival and included 8/14 patients with mutated NFE2L2/NRF2 (Table S1), an important transcription factor in the oxidative stress response pathway. Activating NFE2L2 mutations have been identified in various cancers and are thought to lead to the constitutive activation of oxidative stress pathway genes that benefit tumor cell survival, 17,51 including the autophagy cargo receptor SQSTM1/p62. Overexpression of SQSTM1/p62 sets up a positive feedback loop that further activates NFE2L2 through competitive binding of the NFE2L2 inhibitor KEAP1.…”