Multi-kinase inhibition of STE20 kinases is neuroprotective against chemotherapy-induced axon degeneration

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition resulting from the toxic action of cancer therapies on peripheral neurons. CIPN features axon terminal retraction from target organs leading to a myriad of sensory symptoms such as mechanical and thermal insensitivity, tingling, numbness and burning pain. There are currently no preventative or curative treatments, mostly because the mechanisms leading to axon degeneration upon chemotherapy treatment in humans remain largely unknown. We developed a model of CIPN suitable for high-throughput screening that involves progressive axon degeneration culminating in the death of human iPSC-derived sensory neurons exposed to paclitaxel. Using this model, we screened a library of 192 kinase inhibitors and identified 19 neuroprotective compounds. The top neuroprotective compounds all inhibited members of the STE20 family of kinases; MAP4K4, MAP4K6, and MAP4K7. Genetic and pharmacological inhibition confirmed that simultaneous, but not individual, inhibition of these three kinases is necessary for protection against paclitaxel-induced axonal toxicity in our model, and also in human primary DRG neurons. Importantly, pharmacological inhibitors specific to the STE20 family of kinases did not prevent paclitaxel-mediated killing of three breast cancer cell lines. Transcriptomic studies revealed that it was inhibition of the JNK-c-Jun pathway that prevented cell death and inhibition of the MAP4K-p38 axis that rescued axon degeneration. STE20 kinases are, therefore, a potential therapeutic target for mitigating paclitaxel-induced axon degeneration in sensory neurons while maintaining the therapeutic effects of chemotherapy in cancer patients. Overall design: 28DIV iPSC-derived sensory neurons are treated for 24hrs with paclitaxel in the presence of STE20 inhibitor (GNE-495) to prevent axon degeneration or in the presence of JNK inhibitor (JNK-IN-8) to prevent cell death GSE298389_ProcessedData.xlsx has data for samples GSM9013321-GSM9013356 GSE298389_ProcessedData2.xlsx has data for samples GSM9345116-GSM9345163