Mechanistic insights into the pathogenesis of microtubule‐targeting agent‐induced peripheral neuropathy from pharmacogenetic and functional studies

Abstract

Chemotherapy‐induced peripheral neuropathy (CIPN) is a common dose‐limiting toxicity that affects 30%–40% of patients undergoing cancer treatment. Although multiple mechanisms of chemotherapy‐induced neurotoxicity have been described in preclinical models, these have not been translated into widely effective strategies for the prevention or treatment of CIPN. Predictive biomarkers to inform therapeutic approaches are also lacking. Recent studies have examined genetic risk factors associated with CIPN susceptibility. This review provides an overview of the clinical and pathologic features of CIPN and summarizes efforts to identify target pathways through genetic and functional studies. Structurally and mechanistically diverse chemotherapeutics are associated with CIPN; however, the current review is focused on microtubule‐targeting agents since these are the focus of most pharmacogenetic association and functional studies of CIPN. Genome‐wide pharmacogenetic association studies are useful tools to identify not only causative genes and genetic variants but also genetic networks implicated in drug response or toxicity and have been increasingly applied to investigations of CIPN. Induced pluripotent stem cell‐derived models of human sensory neurons are especially useful to understand the mechanistic significance of genomic findings. Combined genetic and functional genomic efforts to understand CIPN hold great promise for developing therapeutic approaches for its prevention and treatment.

Blood neurofilament light chain as a biomarker for monitoring and predicting paclitaxel-induced peripheral neuropathy in patients with gynecological cancers

“…increased sensitivity to taxane-induced neuropathy support this hypothesis (24). Therefore, high sNfL levels (> 124 pg/ mL) after two cycles of paclitaxel may help predict patients at risk of developing severe PIPN after c om pletion of chemotherapy.…”

Stem Cell‐Based Models for Studying the Effects of Cancer and Cancer Therapies on the Peripheral Nervous System

“…These variants map to proteins involved in RhoGTPase signaling pathways which are essential for axonal guidance and neuronal extension. [ 34 ] This suggests that patients with variants that are more prone to axonal degeneration or have reduced regenerative properties may be more susceptible to peripheral neuropathy. These findings have led to the identification of novel drug targets for paclitaxel‐induced sensory neuropathy that are currently being evaluated in the clinic (NCT03941643, NCT03943498).…”

Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: Approaches with Natural Compounds from Traditional Eastern Medicine

“…In the case of paclitaxel, a taxane-based chemotherapeutic agent, alteration of mitochondrial function was claimed to be responsible for the manifestation of CIPN [ 28 ]. Many other chemotherapeutic agents also induce mitochondrial dysfunction by altering microtubule dynamics [ 29 , 30 , 31 , 32 ]. This effect is exerted by the interaction between the drug and tubulin.…”