(215) Differential Expression of Axonal Transport Related Genes and Pathways in Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Survivors

Abstract

Taxol is a common chemotherapy (CTX) drug that is associated with the development of neuropathy. Paclitaxel-induced peripheral neuropathy (PIPN) is the dose limiting toxicity of this CTX drug. Paclitaxel exerts its therapeutic effect by binding to β-tubulin, which interferes with microtubule dynamics and results in microtubule stabilization, mitotic arrest, and apoptosis of cancer cells. However, microtubules are critical for axonal function and for the transport of essential organelles to distal nerve endings. Disruption of axonal transport (AT) can lead to axonal degeneration and neuropathy. The purpose of this pilot study was to evaluate for differential expression (DE) and perturbations in AT related genes and pathways between breast cancer (BC) survivors who did (n=25) and did not (n=25) develop PIPN. Gene expression in peripheral blood was assayed using RNA-seq. BC survivors with PIPN were significantly older; more likely to be unemployed; reported lower alcohol use; had a higher BMI and a poorer functional status; and had a higher number of lower extremity sites with loss of light touch, cold, and pain sensations, and higher vibration thresholds. No between group differences were found in the cumulative dose of paclitaxel received or in the percentage of patients who had a dose reduction or delay due to PIPN. Three candidate paclitaxel metabolizing genes were DE (i.e., TUBB4B, TUBB2A, RFX2) and two pathways associated with AT were significantly perturbed (i.e., axon guidance, regulation of actin cytoskeleton). This study is the first to provide molecular evidence that a number of axonal transport mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivors with persistent PIPN and suggest genes for validation and as potential therapeutic targets.