Differential Contribution of Neuronal Uptake Transporters to Oxaliplatin Peripheral Neurotoxicity

BACKGROUND Peripheral neurotoxicity afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin therapy. Oxaliplatin preferentially accumulates in and causes toxicity to peripheral sensory neurons present in the dorsal root ganglia (DRG), but mechanistic details of the transporters involved in this process remain uncertain. In the present study, we set out to unambiguously identify these transporter(s) to support the notion that oxaliplatin accumulation in DRGs is a key trigger for the development of peripheral neurotoxicity. METHODS Engineered mouse models with transporter deficiency were used to assess peripheral neurotoxicity by the Von Frey Hair test. Immunofluorescence and primary ex vivo culture of DRGs were performed to determine localization, expression, and function. Pertinent findings were validated in Sprague‐Dawley rats as a secondary model organism, while the translational feasibility of using transport inhibitors to mitigate oxaliplatin‐induced peripheral neurotoxicity was demonstrated in preclinical models of colorectal cancer. RESULTS Comparative in vitro and in vivo association studies revealed that deficiency of OCT2 confers significant protection against acute and chronic peripheral neurotoxicity, but this was not observed for the putative oxaliplatin transporters OCT3, OCTN1, OATP1B2, OATP2B1, and MATE1. Within DRGs, OCT2 was localized to satellite glial cells (SGCs), and accumulation of oxaliplatin in ex vivo cultures of SGCs was prevented by pretreatment with the OCT2 inhibitor, dasatinib. The importance of this transport system was verified in rats, where pretreatment with dasatinib in wild‐type rats recapitulated paw sensitivity phenotypes observed in OCT2‐deficient rats. Dasatinib did not influence the systemic clearance of oxaliplatin, indicating that the observed neuroprotection is directly mediated by inhibition of neuronal transport. At the applied dose and schedule that afford neuroprotection, we found that dasatinib did not negatively affect the antitumor properties of oxaliplatin against colorectal cancer cells in vitro and in vivo. CONCLUSION We identified a previously unrecognized, SGC‐specific pathway of oxaliplatin‐induced neurological injury that is mediated by the organic cationic transporter, OCT2, which can be targeted pharmacologically without compromising the anticancer properties of oxaliplatin. These findings not only shed light on the etiology of oxaliplatin‐induced neurotoxicity, but also provide a rationale for the development of targeted interventions using transporter inhibitors to mitigate a debilitating side effect associated with conventional chemotherapy.