Abstract B029: Targeting non-canonical function of TXNRD1 to overcome platinum resistance by eradicating ovarian cancer stem-like cells
Authors: Martina Towers, Xue Hao, Shruthi Sriramkumar, Wei Zhou, Rugang Zhang
Journal: Cancer Research (2024)

Abstract Introduction: Epithelial Ovarian cancer (EOC) is one of the most fatal gynecological malignancies, with little improvement being made to early-stage diagnostics or treatment options over the years. The standard of care for EOC remains to be platinum-based chemotherapy despite the ultimate relapse which arises with acquired chemoresistance. Accumulating studies show that cancer stem-like cells (CSCs) following initial platinum chemotherapy treatment contribute to the developed chemoresistance and metastasis. Thus, there is an urgent need to develop therapeutic strategies targeting CSCs in EOC. The purpose of this study is to evaluate the efficacy of inhibiting a newly discovered non-canonical function of thioredoxin reductase 1 (TXNRD1) as means of suppressing CSCs through reduction of the platinum-induced senescence-associated secretory phenotype (SASP). Background: DNA damage caused by platinum-based therapies are known to induce senescence in EOC. Senescent cells remain metabolically active and influence the tumor microenvironment through the senescence associated secretory phenotype (SASP). While the tumor cells are senescent, they experience proliferative arrest, however, the SASP promotes the CSCs. Thus, targeting the SASP is a possible strategy for reducing platinum-induced CSCs. The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway plays a key role in promoting the SASP through sensing cytosolic chromatin fragments (CCFs) following DNA damage. Our preliminary data shows that TXNRD1 localizes to CCFs and enhances cGAS activity, contributing to the SASP. We hypothesize that inhibition of TXNRD1 therefore suppresses the SASP. Methods: To investigate the effect of TXNRD1 inhibition on CSCs and the SASP following platinum treatment, TXNRD1 genetic knockdown and use of a small molecule inhibitor, Tri-1, were used. The localization of TXNRD1 and cGAS was analyzed using immunofluorescence. The degree of SASP inhibition was determined by antibody-based cytokine array or qPCR. CSC enrichment was then characterized by ALDH activity, sphere formation, and outgrowth assays. In-vivo models were conducted using ovarian intra-bursal injection in C57BL/6 mice. Results: Our results indicate that conditioned media collected from platinum-induced senescent cells when incubated with naïve cells demonstrated that the SASP components following cisplatin treatment were sufficient to induce the increase in ALDH+ which was reduced by Tri-1. The Tri-1 treatment is sufficient to decrease the ability of ALDH+ sorted cells to form spheroids as well as repopulate and form colonies after extended incubation time after being released from treatment. Tri-1 also synergized with platinum therapy in-vivo, reducing tumor burden in immune-competent mice. Conclusion: Inhibition of TXNRD1 as a method of reducing the SASP suppresses the formation of CSCs following platinum treatment through modulation of the tumor microenvironment. Citation Format: Martina Towers, Xue Hao, Shruthi Sriramkumar, Wei Zhou, Rugang Zhang. Targeting non-canonical function of TXNRD1 to overcome platinum resistance by eradicating ovarian cancer stem-like cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B029.