# High-throughput identification of molecular targets responsible for drug-induced peripheral neuropathies.

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $395,973

## Abstract

Summary
Precision drug therapies have emerged as an effective and increasingly common form of cancer treatment.
These therapies frequently employ multi-kinase inhibitor drugs (MKIs) that each target multiple receptor
tyrosine kinases, sometime in combination with “conventional” cytotoxic chemotherapy drugs. One common
side effect of many cancer drug treatments is damage to the patient's peripheral nervous system, termed drug-
induced peripheral neuropathies (DIPNs). Most of these DIPNs are caused by the “dying back” of distal
sensory axons that innervate the skin, leading to sensory pain and dysfunction. Several commonly used MKIs
induce peripheral neuropathies, however, specific targets responsible for these painful DIPNs are unknown. To
address this knowledge gap, we established a high-content screening approach that allows rapid identification
of neurotoxic compounds in zebrafish. Using this approach, we showed that three MKIs known to produce
DIPNs in patients led to the reduced density of distal cutaneous somatosensory axons in zebrafish. Live
imaging demonstrated that axon retraction is the cellular basis for this reduced dermal axon density, consistent
with a “dying back” pathophysiology. Furthermore, these results were replicated in mouse dorsal root ganglia
neurons. Initial screening for MKI targets underlying this neurotoxic effect found that loss of the receptor
tyrosine kinase c-Kit, but not other shared kinase targets, led to reduced cutaneous axon density. c-Kit is
expressed in a subset of vertebrate sensory neurons in embryos and adults and its ligand SCF is expressed in
the skin, but the specific role of this ligand-receptor in axon maintenance or DIPNs has not been defined.
Importantly, application of one of these MKIs in c-kit mutants did not exacerbate axon density loss, indicating
that Kit is a major target for an MKI in the peripheral nervous system. Based on preliminary data we propose in
Aim 1 to: 1) implement a high-content screening approach in zebrafish to identify MKIs that induce distal
sensory axon toxicity in vivo and then identify their molecular targets; and 2) validate these results in
mammalian DRG culture. Aim 2 will characterize the downstream mechanisms underlying the neurotoxicity of
c-Kit receptor loss-of-function described in our preliminary data. Our work will identify and characterize the
molecular targets and cellular bases of painful MKI-induced peripheral neurotoxicity. This, in turn, will provide
new pathways and points of potential intervention to study in the context of a major, but unaddressed, clinical
problem in cancer drug therapies. In addition, we will also establish a workflow and reagents for future study of
candidate targets of DIPNs.

## Key facts

- **NIH application ID:** 10371819
- **Project number:** 1R21CA260025-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alex Nechiporuk
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $395,973
- **Award type:** 1
- **Project period:** 2022-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371819

## Citation

> US National Institutes of Health, RePORTER application 10371819, High-throughput identification of molecular targets responsible for drug-induced peripheral neuropathies. (1R21CA260025-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10371819. Licensed CC0.

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