Abstract 4796: Chemotherapy induced senescence drives peripheral neuropathy

Abstract

Chemotherapy is a mainstay of cancer therapy. Unfortunately, while chemotherapy can profoundly impact disease free survival, it’s often accompanied with devastating side effects, including peripheral neuropathy. Indeed, 30-40% of patients treated with neurotoxic chemotherapy develop long-term and often debilitating chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, there are currently no preventative measures for CIPN and while it is transitory in some patients, for others the side effects can persist for months or even years after the cessation of chemotherapy. Recent work suggests that cellular senescence, which is robustly induced by chemotherapy, contributes to CIPN. Senescent cells are typically characterized by increased CDKn2a (i.e., p16) expression, increased SA-β-gal hydrolyzation, and expression of the senescence-associated secretory phenotype (SASP) that can influence multiple cell types in the microenvironment. Through utilization of a mouse model that employs paclitaxel (PTX), we find that PTX robustly induces senescence in the hindpaws and dorsal root ganglia (DRG) of mice that display loss of peripheral axons and decreased response to mechanical stimuli. To address the role of senescence in CIPN, we utilized the INKATTAC mouse that allows for inducible elimination senescent cells. Using this model, we find that the elimination of senescent cells rescues CIPN. Further, the use of senolytics, drugs that kill senescent cells, also rescues CIPN, raising the possibility that we can treat patients with CIPN. To address the mechanism behind CIPN we have carried out single cell RNA-Seq to identify the population of senescent cells senescing in response to chemotherapy. These analyses will allow us to understand the mechanisms that drive CIPN and may lead to new treatments for patients suffering from CIPN. Citation Format: Taylor Malachowski, Ganesh Raut, Satarupa Mullick Bagchi, Shelia Stewart. Chemotherapy induced senescence drives peripheral neuropathy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4796.