NFE2L2 mutation

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.

A gain-of-function truncation mutant, NFE2-226aa, retains the capacity to interact with ITCH but is no longer degraded. Rather, NFE2-226aa protects wt NFE2 from ITCH-dependent degradation, resulting in enhanced NFE2 activity.

Collectively, available evidence from various studies positions multi-omics profiling as a critical clinical tool. It enables the classification of tumors by dominant immunometabolic phenotype, thereby paving the way for biomarker-driven trials that rationally combine metabolic inhibitors with immunotherapy to overcome resistance.

Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_Cys151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).

Furthermore, in vivo studies using KRAS-mutant H358 xenograft models confirm the potent anti-tumor effects of EB. Collectively, our findings establish that EB triggers ferroptosis in KRAS-mutant NSCLC by activating the Keap1-Nrf2/HO-1 pathway, suggesting a promising therapeutic strategy for this challenging malignancy.

NFE2 gene mutations in MPNs were predominantly frameshift mutations. NFE2 gene mutations were correlated with older age, elevated levels of several inflammatory factors (including TNF-α、IFN-γ、IL-10、IL-12P70、IL-17) , and they mostly occurred in late-stage of MPNs.

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.

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

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.

NFE2L2 mutations were more common in the middle thoracic esophagus, appeared to be associated with tumor progression, and were linked to poor prognosis.