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A human iPSC-derived sensory neuron platform for high-throughput discovery of neuroprotectants against chemotherapy-induced peripheral neuropathy

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of cancer treatment, yet the lack of predictive human models has hindered therapeutic progress. We have established a scalable model of paclitaxel-induced axon degeneration and neurotoxicity in iPSC-derived sensory neurons, suitable for high-throughput discovery of neuroprotective compounds. Using this platform, we screened 192 kinase inhibitors and identified 19 hits that commonly inhibited three STE20 kinases - MAP4K4, MINK1, and TNIK. Genetic knockdown revealed that multi-kinase inhibition of STE20 kinases is required for neuroprotection against paclitaxel. Moreover, selective pharmacological inhibition of STE20 kinases rescued paclitaxel-induced axon degeneration in iPSC-derived sensory neurons and primary human DRG, as well as preserved intraepidermal nerve fiber density in a mouse model of CIPN. These results establish a translational human sensory neuron platform for target and drug discovery in CIPN.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Sensory Processing Neuron

DISEASE(S): Sensory Peripheral Neuropathy

SUBMITTER: Marian Kalocsay

LAB HEAD: Clifford Woolf

PROVIDER: PXD074954 | Pride | 2026-04-03

REPOSITORIES: Pride

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			Action	DRS
	3138_CM_ReN_18plx_Aug2024_Fr1_C_000574_psc.mzIdentML	Mzid
	3140_CM_ReN_18plx_Aug2024_Fr2_C_000575_psc.mzIdentML	Mzid
	3142_CM_ReN_18plx_Aug2024_Fr3_C_000576_psc.mzIdentML	Mzid
	3144_CM_ReN_18plx_Aug2024_Fr4_C_000577_psc.mzIdentML	Mzid
	3146_CM_ReN_18plx_Aug2024_Fr5_C_000578_psc.mzIdentML	Mzid

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Project description:The microtubule-stabilizing drug paclitaxel remains standard of care for various solid malignancies but frequently leads to chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a leading cause for premature treatment termination and a significantly reduced quality of life in long-term cancer survivors. The molecular mechanisms of neuro-axonal degeneration, neuroinflammation and pain in patients treated with paclitaxel remain incompletely understood, and there are currently no predictive biomarkers or preventive treatments. We used human iPSC-derived sensory neurons exposed to paclitaxel to comprehensively model the pathophysiology of CIPN. Neurotoxicity was assessed over time using viability assays and sequential RNA sequencing as well as deep proteome and lipidomic analyses. We observed a time and dose-dependent decline of cell viability at clinically relevant paclitaxel doses. Sequential RNA sequencing defined JUN as an early immediate gene, followed by the overexpression of genes of the neuronal stress response (e.g., ARID5A, WEE1, DUSP16, GADD45A), neuronal injury and apoptotic pathways (e.g., ATF3, HRK, BBC3 [PUMA], BCL2L11 [BIM], CASP3), neuroinflammation and nociception (CALCB, MMP10, IL31RA, CYSLTR2, C3AR1, TNFRSF12A) and neuronal transduction (e.g., CAMK2A, STOML3), while key enzymes of lipid biosynthesis were markedly downregulated (e.g., LSS, HMGCS1, HMGCR, DHCR24). Deep proteome analyses following 48 hours of exposure to 100nM paclitaxel revealed a strong correlation of differentially expressed RNA with proteins, and a marked degradation of essential axonal transport proteins such as kinesins, stathmins and scaffold proteins. Consistent with the downregulation of rate-limiting enzymes of lipid biosynthesis, lipidome analysis confirmed deregulation of neuronal lipid homeostasis. In summary, paclitaxel induces transcriptomic and proteomic signatures of the neuronal stress response, neuroinflammation, nociception and disturbed metabolism. These may explain, in part, the clinical phenotype of sensory loss, hypersensitivity and neuropathic pain frequently observed in patients suffering from CIPN, but constitute pharmacologically addressable targets

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A human iPSC-derived sensory neuron platform for high-throughput discovery of neuroprotectants against chemotherapy-induced peripheral neuropathy

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