KEAP1 mutation

In this review, we systematically summarize and discuss the molecular mechanisms underlying the tumor-suppressive function of KEAP1, the spectrum and functional consequences of cancer-associated KEAP1 mutations, the clinical implications of KEAP1 alterations as prognostic biomarkers, and potential therapeutic strategies targeting the KEAP1-NRF2 axis. Our work provides comprehensive insights into the multifaceted roles of KEAP1 in cancer biology and its therapeutic implications.

P1, N=1, Terminated, M.D. Anderson Cancer Center | N=52 --> 1 | Trial completion date: Dec 2026 --> Mar 2026 | Recruiting --> Terminated; Sponsor discontinued the trial

NSCLCs harboring ECD-ERBB2 mutations are associated with a unique clinico-genomic phenotype and improved outcomes with first-line chemoimmunotherapy. These findings have implications for optimizing treatment strategies in this disease.

In first-line ICI-treated stage IV NSCLC, KRAS-KEAP1 co-mutation, not KRAS or KEAP1 alone, identifies patients at high risk of early failure, whereas BRAF was associated with longer TTF. These findings highlight the importance of co-mutation profiling and warrant prospective validation with integrative models incorporating PD-L1 and TMB.

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.

For large cell neuroendocrine carcinomas, the anti-Rb antibody can be helpful in determining patient treatment, in conjunction with KRAS, STK11, and KEAP1mutation testing. Finally, clones of these antibodies can show different results in terms of sensitivity and specificity, which are discussed in this work.

P1, N=52, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2030 --> Dec 2026

P2, N=100, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Phase classification: P3 --> P2 | N=280 --> 100 | Trial completion date: Mar 2031 --> Dec 2027 | Trial primary completion date: Aug 2027 --> Dec 2026

A novel EGFR mSig that captures the transcriptional footprint of EGFR activation revealed a subset of EGFR WT LUADs with "mt-like" features. mSig refines LUAD taxonomy beyond mutation-only pie-chart models by incorporating lineage and co-mutation context. Lineage-directed stratification with co-alteration identifies clinically relevant groups across EGFR and RAS states and highlights new treatment opportunities for patients currently considered "oncogene-negative.".

A detailed prognostic factor analysis for overall survival and progression-free survival in selected groups of advanced non-small-cell lung cancer patients under chemo- or mono-immunotherapy identified five independent parameters: initial ECOG of zero, non-elevated LDH, non-elevated CRP, pretreatment PD-L1 positivity and absence of KEAP1-mutation. Our findings are especially helpful of estimating early treatment failure with aggressive lung cancer progression. This important investigation will be prospectively confirmed in a larger, more unselected population at our Cancer Centre.

© 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

These findings suggest that KAE alleviates ALI by targeting Keap1 Arg415, disrupting Keap1-mediated inhibition of Nrf2, thereby promoting its nuclear translocation and activating antioxidant and anti-ferroptosis pathways. This work highlights KAE's therapeutic potential and provides a theoretical basis for developing Keap1-Nrf2-targeted drugs.