ValMet protects oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the c.196G>A polymorphism (ValMet) as a critical factor in CIPN development. Using humanized transgenic mouse models, we demonstrated that the Met allele of the functional ValMet polymorphism in confers protection against oxaliplatin-induced sensory deficits, whereas the Val allele increases susceptibility to neuropathy. Mechanistic studies revealed that this protection operates through modulation of p75NTR-mediated signaling pathways and neuroinflammatory responses. On the basis of these findings, we evaluated two therapeutic strategies: the p75NTR modulator LM11A-31 and a compound we have developed, CN016. Both agents exhibited notable efficacy in alleviating oxaliplatin-induced neuropathy, particularly in genetically susceptible Val/Val carriers. LM11A-31 normalized neurotrophic signaling and preserved sensory structures, and CN016 effectively modulated neuroinflammatory pathways through macrophage inhibition at an optimal dose of 20 mg/kg. The Met variant shows about 49% prevalence in East Asian populations and 1 to 20% in other ethnic groups, suggesting population-specific susceptibility to CIPN. These findings establish genetic variation as a crucial determinant of CIPN risk and validate two promising therapeutic approaches, providing a foundation for personalized neuroprotective strategies in cancer treatment.