Monomethyl auristatin E and paclitaxel use different mechanisms to alter intracellular calcium signaling

Antibody-drug conjugates (ADCs) are a promising class of targeted cancer therapies that deliver cytotoxic agents to cancer cells. Although designed to reduce side effects, ADCs utilizing a microtubule-targeting agent, exemplified by monomethyl auristatin E (MMAE), as the drug cargo, frequently induce chemotherapy-induced peripheral neuropathy (CIPN) at rates comparable to taxanes like paclitaxel (PTX). Despite their clinical success, ADC-associated neurotoxicity remains a significant challenge, necessitating a deeper mechanistic understanding and potential neuroprotective strategies. This study examines the neurotoxic effects of MMAE and PTX and evaluates lithium as a protective agent. Zebrafish models demonstrated that MMAE exhibits greater neurotoxicity than PTX, yet lithium co-treatment significantly improved survival. In human cell lines PTX treatment transiently increased intracellular calcium levels before reducing calcium signaling, whereas MMAE induced an immediate and sustained reduction in calcium signaling. Despite these distinct effects, lithium mitigates functional changes in both cases. The calcium binding protein neuronal calcium sensor 1 (NCS-1) is an essential component of the PTX pathological pathway; however, docking and immunoprecipitation assays showed that MMAE and PTX bind to NCS-1 at different sites, leading to differential impacts on calcium homeostasis. PTX enhances NCS-1 interaction with the inositol trisphosphate receptor (ITPR), whereas MMAE does not, underscoring mechanistic differences in their neurotoxicity. Lithium's ability to prevent neuronal dysfunction suggests it as a prophylactic agent against CIPN. By elucidating how these drugs disrupt calcium homeostasis, this study provides critical insights into ADC-induced neurotoxicity and highlights lithium as an intervention to enhance chemotherapy tolerability and patient quality of life.