Identification of small molecules that mitigate vincristine-induced neurotoxicity while sensitizing leukemia cells to vincristine.

Vincristine is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose-limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing vincristine-induced neurotoxicity without compromising its anticancer effects would be ideal. Here we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to vincristine, and that concomitant administration of vincristine with inhibitors of NHP2L1 increases vincristine cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases vincristine effects on human induced pluripotent stem cell (hiPSC)-derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing vincristine's antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.