Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy

• DOI: 10.1172/jci.insight.164646
• Publication Date: 2023-06-22T16:21:50Z
• Authors: Yang Li; Thomas Drabison; Mahesh Nepal; Richard H. Ho; Alix F. Leblanc; Alice A. Gibson; Yan Jin; Wenjian Yang; Kevin M. Huang; Muhammad Erfan Uddin; Mingqing Chen; Duncan F. DiGiacomo; Xihui Chen; Sobia Razzaq; Jeffrey R. Tonniges; Dana M. McTigue; Alice S. Mims; Maryam B. Lustberg; Yijia Wang; Amanda B. Hummon; William E. Evans; Sharyn D. Baker; Guido Cavaletti; Alex Sparreboom; Shuiying Hu
• Keywords: Neurotoxicity

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes dose-limiting peripheral neurotoxicity. There no clinically effective preventative vincristine-induced sensory neurotoxicity (VIPN), and mechanistic details this side effect remain poorly understood. We hypothesized VIPN dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using xenobiotic transporter screen, we identified OATP1B3 as neuronal regulating uptake vincristine. In addition, genetic or pharmacological inhibition murine orthologue OATP1B2 protected mice from various hallmarks - including mechanical allodynia, thermal hyperalgesia, changes digital maximal action potential amplitudes morphology without negatively affecting plasma levels antitumor effects Finally, α-tocopherol an untargeted metabolomics analysis circulating endogenous biomarker function, it could serve companion diagnostic to guide dose selection OATP1B-type transport modulators given combination with prevent VIPN. Collectively, our findings shed light fundamental basis provide rationale clinical development inhibitors debilitating effect.