KEAP1 mutation

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.

This review summarizes the associations between genetic mutations and metastatic sites, explores underlying molecular mechanisms, and discusses mutation-based risk prediction and personalized therapeutic strategies. With multi-omics integration and further clinical research, genetic profiling may become a key tool for guiding metastasis prevention, early intervention, and treatment optimization in NSCLC.

Although allosteric GLS inhibitors such as BPTES (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide) and later-generation analogs such as CB-839 (Telaglenastat) have pharmacologically validated this target, their clinical utility has been constrained by suboptimal drug-like properties, including poor solubility and bioavailability...This biochemical potency translated to a functional effect in a cellular model of glutamine dependence, as evidenced by a significant depletion of intracellular glutamate pools in LDK378-resistant (LR) cells. Furthermore, TRG-192 demonstrated a favorable preclinical safety profile in initial toxicological assessments. Collectively, these data-encompassing potent target engagement, functional on-target activity, and preliminary safety-provide a compelling rationale for the advancement of TRG-192 into in vivo efficacy studies.

TP53-d and STK11 mutations might have a predictive impact in localized-stage NSCLC, but further investigation is needed. KEAP1 mutations associate with worse outcomes, especially in patients receiving adjuvant chemotherapy.

TTF-1 negativity identifies a subset of LUAD with worse outcomes to immunotherapy, chemo-immunotherapy, and KRASG12C inhibitors.

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.

Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.

As an interpretable model integrating readily-accessible and crucial clinical-genomic predictors, PRIME achieves enhanced performance, allowing for early outcome prediction, refined risk stratification, and personalized clinical decision-making.

In contrast, NRF2 activators, such as bardoxolone methyl (CDDO-Me), sulforaphane, and dimethyl fumarate, exhibit chemopreventive effects by enhancing detoxification and mitigating oxidative DNA damage during early tumorigenesis...Therefore, understanding the temporal and contextual effects of NRF2 signaling is crucial for therapeutic design. The aim of this review is to examine how pharmacological modulation of NRF2 influences the invasive and metastatic dimensions of tumor progression, in addition to discussing its potential integration into TNM-based prognostic and treatment frameworks.

In this large, multicenter Turkish real-world cohort, the TGA spectrum broadly mirrors global patterns while revealing local nuances; EGFR mutations were more frequent than expected in SCC, and nationwide NGS adoption is accelerating. Limitations include retrospective design, non-centralized PD-L1 testing, and missing data. Prospective, standardized studies integrating outcomes and resistance mechanisms are warranted to refine regional precision oncology.