KEAP1 mutation

Emerging evidence supports rational combination strategies, including parallel inhibition of epidermal growth factor receptor, protein tyrosine phosphatase non-receptor type 11 or SOS1 and vertical blockade of the mitogen-activated protein kinase-extracellular signal-regulated kinase or phosphatidylinositol 3-kinase-mechanistic target of rapamycin cascades; immunotherapies such as checkpoint blockade, T-cell receptor (TCR)-T cells, bispecific T-cell engagers or cytokine-armed oncolytic viruses; metabolic interventions targeting macropinocytosis or autophagy; as well as radiotherapy...Precision approaches that integrate multiomics profiling with longitudinal circulating tumour DNA analysis enable biomarker-guided patient selection (eg, based on STK11 and KEAP1 comutations) and support therapeutic adaptations, including sequencing strategies and intermittent dosing. Thus, network-level KRAS interception combined with biomarker-driven, clonal evolution-informed trial design offers a path towards sustained control of KRAS-driven cancers.

These findings suggest that UXS1 loss is synthetic lethal with NRF2 activation and may be a promising target for therapy. See related article by Gebru et al., p. 4806.

P1, N=22, Active, not recruiting, National Cancer Institute (NCI) | N=85 --> 22 | Trial completion date: Jun 2026 --> Nov 2026 | Trial primary completion date: Jun 2026 --> Nov 2025

In PD-L1 TPS ≥ 50% NSCLC patients treated with pembrolizumab, our results suggest an improved PFS in patients predicted to be KEAP1/NFE2L2 mutated.

The chymotrypsin of fish fed the A25T10 diet was significantly higher than those in other groups (p < 0.05)...In this study, taurine supplementation can down-regulate the expression of intestinal pro-inflammatory factors (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8)) and up-regulate the expression of anti-inflammatory factor interleukin-10 (IL-10), enhance intestinal immunity, and improve intestinal digestion and absorption. Therefore, the addition of 1-1.5% taurine to low-fishmeal feeds can improve the growth performance of golden pompano.

Further research is therefore essential to define biomarkers of Nrf2 dependency, optimize therapeutic windows, and integrate pathway modulation into precision medicine frameworks. A deeper understanding of this regulatory axis may ultimately transform Nrf2 from a compelling molecular target into a cornerstone of redox-based precision therapeutics.

P1, N=41, Terminated, Novartis Pharmaceuticals | N=140 --> 41 | Trial completion date: Jul 2027 --> Oct 2025 | Recruiting --> Terminated | Trial primary completion date: Jul 2027 --> Oct 2025; The trial was terminated due to a business decision and not as a result of any safety concerns

Similarly, inhibition of Nrf2 using ML385 markedly diminished RBG-induced improvements in neurological behavior in tMCAO rats. Our results identify RBG as a new modulator of the Keap1-Nrf2-TFR1/ARE axis and suggest that RBG has promising neuroprotective potential against CIRI through its effects on microglial homeostasis.

Approximately 280 eligible patients, aged ⩾18 years, will be randomized 1:1 to receive tremelimumab 75 mg plus durvalumab 1500 mg plus carboplatin AUC 5/6 or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles, followed by maintenance durvalumab 1500 mg plus pemetrexed 500 mg/m2 Q4W, with an additional dose of tremelimumab 75 mg at week 16 and optional further dose at month 24; or pembrolizumab 200 mg plus carboplatin AUC 5/6 or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 Q3W for four cycles, followed by maintenance pembrolizumab 200 mg plus pemetrexed 500 mg/m2 Q3W. Results will help to inform clinical practice and establish a biomarker-driven treatment strategy for these subtypes of mNSCLC with high unmet need. ClinicalTrials.gov identifier: NCT06008093 (registration date: August 17, 2023).

RICTOR mutations in lung adenocarcinoma define a molecularly distinct subgroup characterized by preferential co-occurrence with EGFR, KRAS, and TP53, as well as a broader spectrum of genomic alterations. These findings support the view that RICTOR functions within complex oncogenic contexts and warrant further investigation in larger, multi-institutional cohorts.

These findings support integrating multiple biomarkers to improve risk stratification and personalize treatment in unresectable stage III NSCLC. The study is registered on www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT04392505).

Lastly, we utilized one small molecule inhibitor, SMARCA2-IN-8, to inhibit progression of Keap1-deficient NSCLC murine models. Together, our study highlight the synthetic lethal relationship between Keap1 and PHF10, and provide targeting PHF10-SMARCA2 complex as an effective option to hit Keap1-deficient NSCLC.