KEAP1 mutation

This review focuses on targeting NRF2-driven metabolic dependencies as synthetic lethal vulnerabilities, spanning pathways such as glutaminolysis, redox imbalance, cystine metabolism, nucleotide biosynthesis and ER proteostasis. We also highlight emerging strategies, including allosteric KEAP1 activators, and discuss key challenges in translating these approaches into effective therapies.

P1, N=54, Recruiting, M.D. Anderson Cancer Center | Trial completion date: May 2026 --> Jun 2028 | Trial primary completion date: May 2026 --> Mar 2028

Beyond immunotherapy, STK11 mutations confer poor outcomes across targeted therapies, including KRAS G12C inhibitors, with KEAP1 co-mutation serving as a strong negative predictor of efficacy. In this review we present an overview of STK11 function and its role in tumor biology, highlight the prognostic and predictive potential of STK11 mutations in the context of NSCLC treatment and summarize the emerging treatment strategies.

In plasma, twelve genes were consistently detected, and SHOC2, YAP1, LZTR1, RGS3, and ZDHHC7 were significantly upregulated at week 6. Low tumor LIFR expression was associated with poorer survival, supporting its potential as a prognostic biomarker and highlighting the feasibility of plasma-based gene expression monitoring.

Targeting dysregulated SPP1 improved cisplatin sensitivity and suppressed tumor invasion and metastasis in NRF2-hyperactivated HNSCC, underscoring the therapeutic potential of SPP1 inhibitors to improve patient outcomes.

This study demonstrated the broad spectrum of variants in STK11, KEAP1 and TP53 in routine panel-based DNA NGS, with 70.3% of the samples without AGA showing a potential clinically relevant mutation in TP53, STK11 and/or KEAP1.

KEAP1 knockdown promotes NRF2 upregulation and HIF-1α protein accumulation in HNSCC independent of mRNA changes, suggesting protein-level or redox-mediated crosstalk between oxidative stress and hypoxia pathways.

Cellular immunotherapies (tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptor-T), antibody-drug conjugates, and vaccines offer complementary means to restore antitumor immunity. Advancing the field will require biomarker-driven patient selection and rational combinations to overcome AR and achieve more durable, personalized immunotherapy outcomes in NSCLC.

Mechanistically, the combination suppresses AKT activity and promotes AKT degradation, ultimately leading to apoptotic cell death. Taken together, these findings support the potential of combined Canagliflozin and Brusatol treatment as an effective therapeutic approach for LKB1-KEAP1 co-mutant NSCLCs.

The bidirectional crosstalk between ferroptosis and antitumor immunity within the lung tumor microenvironment (TME) is systematically dissected, with detailed characterization of how nanomedicine-mediated ferroptosis modulation optimizes this crosstalk to drive therapeutic pulmonary immune remodeling. Finally, key future directions for the advancement of precision ferroptosis medicine are outlined, including spatiotemporally controlled ferroptosis activation, biomarker-driven patient stratification panels, and rational strategies to balance therapeutic efficacy and pulmonary safety throughout clinical translation.

In this real-world cohort of actionable mutation-negative NSCLC cases, we did not detect significant prognostic associations for TP53, STK11, and KEAP1 mutations, and their incidence was similar between de novo and recurrent disease. These findings underscore the need for larger studies to evaluate the prognostic utility of these mutations in this clinical context.

Recurrence timing alone insufficiently reflects clonal relationships. Genomic profiling offers a reliable framework for distinguishing between recurrence types and guiding HCC management.