Abstract 5145: Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is the most lethal type of lung cancer. The uniqueness of this tumor consists of an initial exquisite response to chemotherapy. However, at relapse, which occurs nearly in all patients, the tumor is resistant to all available therapies, causing a premature death of the patient. Despite the addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy, response rates are modest and only a very small fraction of SCLC patients responds to these therapies. The mechanistic basis for acquired chemoresistance and impaired immunogenicity in SCLC remains to be elucidated. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. ATAC-seq and ChIP-seq analyses revealed a significant increase in chromatin accessibility of TREX1 gene locus in drug resistant SCLC cells. Depletion of TREX1 in SCLC cells caused the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway due to the cytoplasmic accumulation of DNA damage-associated double-stranded DNA (dsDNA) and micronuclei. Furthermore, targeting TREX1 induced an innate immune response and re-sensitized chemoresistant SCLC cells to chemotherapy. These findings suggest that TREX1 upregulation may be an important mediator of cGAS/STING pathway inactivation in cancer, contributing to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to potentiate the efficacy of chemotherapy and immunotherapy in chemoresistant and immunologically ‘cold’ tumors, such as SCLC. Citation Format: Takahiko Murayama, Navin R. Mahadevan, Tetsuo Tani, Xueying Ma, Hideo Watanabe, David A. Barbie, Israel Cañadas. Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer. [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 5145.