Abstract
Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays an initial exquisite response to chemotherapy; however, at relapse, the tumor is highly resistant to subsequent available therapies. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. Assay for transposase-accessible chromatin using sequencing and chromatin immunoprecipitation sequencing revealed a significant increase in chromatin accessibility and transcriptional activity of TREX1 gene locus in chemoresistant SCLCs. Analyses of human SCLC tumors and patient-derived xenografts (PDX) also showed an increase in TREX1 expression in postchemotherapy samples. TREX1 depletion caused the activation of cyclic GMP-AMP synthase stimulator of interferon gene pathway due to cytoplasmic accumulation of damage-associated double-stranded DNA, inducing immunogenicity and enhancing the sensitivity of drug-resistant cells to chemotherapy. These findings suggest TREX1 upregulation may partially contribute to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to enhance antitumor immunity and potentiate the efficacy of chemotherapy and/or immunotherapy in chemoresistant SCLCs. Significance: In this study, we show that targeting TREX1 induces an innate immune response and resensitizes SCLC cells to chemotherapy, representing a promising novel target for "immunologically" cold tumors, such as SCLC.
Original language | English |
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Pages (from-to) | 2399-2414 |
Number of pages | 16 |
Journal | Cancer Research Communications |
Volume | 4 |
Issue number | 9 |
Early online date | Aug 23 2024 |
DOIs | |
State | Published - Sep 1 2024 |
Keywords
- Animals
- Cell Line, Tumor
- Drug Resistance, Neoplasm/genetics
- Exodeoxyribonucleases/genetics
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Immunity, Innate/drug effects
- Lung Neoplasms/genetics
- Mice
- Phosphoproteins/genetics
- Small Cell Lung Carcinoma/genetics
- Xenograft Model Antitumor Assays