Targeting TREX1 Induces Innate Immune Response in Drug-Resistant Small-Cell Lung Cancer

Takahiko Murayama, Navin R. Mahadevan, Catherine B. Meador, Elena V. Ivanova, Yuqiao Pan, Erik H. Knelson, Tetsuo Tani, Jun Nakayama, Xueying Ma, Tran C. Thai, Yin P. Hung, William Kim, Hideo Watanabe, Kathy Q. Cai, Aaron N. Hata, Cloud P. Paweletz, David A. Barbie, Israel Cañadas

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish
Pages (from-to)2399-2414
Number of pages16
JournalCancer Research Communications
Volume4
Issue number9
Early online dateAug 23 2024
DOIs
StatePublished - 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

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