KEAP1 mutation

The study further examines how oncogenic mutations in genes like EGFR, KRAS, TP53, KEAP1, and IDH1 reshape ferroptosis susceptibility or resistance through alterations in metabolic pathways, redox homeostasis, and tumor microenvironment interactions. By highlighting mutation-specific sensitivities, this work underscores the potential of ferroptosis-targeted strategies to surmount therapeutic resistance, synergize with conventional treatments like chemotherapy and immunotherapy, and drive precision oncology forward, paving the way for enhanced clinical outcomes across a broad spectrum of cancers.

Dynamic and active immune recruitment, indicated by immune-hot TME and high TLS score, was predictive of ICI benefit in patients with LUAD. Further prospective studies are warranted to expand to other treatment combinations with PD-(L)1 inhibitors.

Molecular docking further revealed stable interactions of PLD with KEAP1 and NRF2, with Arg483 identified as a key residue mediating KEAP1-NRF2 and PLD-KEAP1 binding, suggesting that KEAP1 modulates NRF2 stability and cellular susceptibility to ferroptosis. Collectively, these results indicate that PLD partially inhibits breast cancer growth through KEAP1/NRF2-mediated ferroptosis, highlighting a novel mechanism underlying its anti-tumor activity.

Notably, depleting these co-dependencies, such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.

Immunohistochemistry of clinical lung adenocarcinoma samples showed that high KAT6A expression correlated with advanced tumor stage and shorter overall survival. These findings suggest that KAT6A regulates oxidative stress via the Keap1-Nrf2 pathway, thereby promoting malignant progression in lung adenocarcinoma, and may serve as a potential prognostic biomarker.

In this single-center, real-world, retrospective analysis, among the 38 patients with advanced NSCLC receiving KRAS G12C inhibitors, a never or light smoking history, poor performance status, and the presence of tumor pathogenic KEAP1 mutations were associated with worse clinical outcomes. Within the limitations of the study, clinicians should consider these variables when formulating treatment for KRAS G12C-mutant NSCLC.

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

Except for age, histologic diagnosis, and liver metastasis, long-term survival is not correlated with baseline variables. Approximately a quarter of progress after 2 years of disease control.

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.