NFE2L2 mutation

This review focuses on targeting NRF2-driven metabolic dependencies as synthetic lethal vulnerabilities, spanning pathways such as glutaminolysis, redox imbalance, cystine metabolism, nucleotide biosynthesis and ER proteostasis. We also highlight emerging strategies, including allosteric KEAP1 activators, and discuss key challenges in translating these approaches into effective therapies.

Moreover, alterations in CCND1 and FGF family genes were associated with poor prognosis, highlighting their potential roles as prognostic biomarkers and therapeutic targets in ESCC. III.

These findings suggest that NFE2L2-mutated urothelial carcinomas frequently have concomitant squamous and myxoid features, aggressive behaviour and high PD-L1 expression. Recognition of the NFE2L2-mutated urothelial carcinomas may have diagnostic and prognostic utility, particularly with immunotherapy and possible targeted therapy against the NRF2 signalling pathway. Further investigation with larger cohorts is warranted to expand the data surrounding NFE2L2 mutations in urothelial carcinoma.

The retention of RB1 and the presence of the NFE2L2 mutation distinguish this entity from classic SCLC, supporting a reclassification as high-grade NSCLC. Recognition of this molecular subset is vital, as NFE2L2 mutations are theoretically linked to resistance to standard platinum-based regimens, potentially necessitating therapeutic strategies distinct from standard SCLC algorithms.

P1, N=54, Recruiting, M.D. Anderson Cancer Center | Trial completion date: May 2026 --> Jun 2028 | Trial primary completion date: May 2026 --> Mar 2028

Targeting dysregulated SPP1 improved cisplatin sensitivity and suppressed tumor invasion and metastasis in NRF2-hyperactivated HNSCC, underscoring the therapeutic potential of SPP1 inhibitors to improve patient outcomes.

These findings show that PYR functionally restores KEAP1-mediated NRF2 degradation of select NRF2Mut through a glue-like effect and overcomes therapy resistance in ESCC. Although the proposed glue-like mechanism remains hypothetical, this work supports further investigation into the NRF2-KEAP1 interaction and may inform the development of KEAP1-targeted strategies for NRF2Mut cancers, including ESCC.

P2, N=54, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Apr 2027

Clinically, high SMURF2 expression correlates with improved survival in patients with GBM exhibiting constitutive NRF2 activation. These findings uncover a novel axis of NRF2 regulation and highlight SMURF2 as a potential therapeutic target for NRF2-driven malignancies.

Nrf2 maintained its association with the outer mitochondrial membrane, thus exerting its protective role. All mitochondrial modifications were observed 24 h after treatment and disappeared after 48 h, demonstrating that cells promptly respond to the O3-driven oxidative stress, effectively restoring homeostasis.

© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.