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

Takahiko Murayama1,2, Navin R Mahadevan3,4, Catherine B Meador5

  • 1Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Cancer Research Communications
|August 23, 2024
PubMed

Insights

Targeting TREX1 in small-cell lung cancer (SCLC) resensitizes resistant tumors to chemotherapy. Inhibiting TREX1 induces an immune response, offering a novel strategy for treating chemoresistant SCLC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Small-cell lung cancer (SCLC) exhibits initial chemotherapy sensitivity followed by acquired resistance.
  • Chemoresistant SCLC poses a significant clinical challenge due to limited effective therapeutic options.
  • The molecular mechanisms underlying SCLC chemoresistance are not fully understood.

Purpose of the Study:

  • To investigate the role of three prime repair exonuclease 1 (TREX1) in SCLC chemoresistance.
  • To explore TREX1 as a potential therapeutic target for overcoming SCLC drug resistance.
  • To evaluate the impact of TREX1 inhibition on tumor immunogenicity and chemotherapy sensitivity.

Main Methods:

  • Analysis of TREX1 expression in chemoresistant SCLC models and patient samples.
  • Assay for transposase-accessible chromatin using sequencing (ATAC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to assess TREX1 gene regulation.
  • TREX1 depletion studies to evaluate effects on DNA sensing pathways and chemotherapy sensitivity.
  • Assessment of STING pathway activation and double-stranded DNA accumulation.

Main Results:

  • TREX1 expression is significantly upregulated in chemoresistant SCLC.
  • Increased chromatin accessibility and transcriptional activity of the TREX1 gene locus were observed in resistant cells.
  • TREX1 depletion activated the cGAS-STING pathway, leading to cytoplasmic accumulation of double-stranded DNA.
  • Inhibition of TREX1 enhanced SCLC cell immunogenicity and resensitized resistant cells to chemotherapy.

Conclusions:

  • TREX1 upregulation contributes to SCLC chemoresistance and cell survival.
  • Targeting TREX1 can induce an innate immune response and resensitize SCLC to chemotherapy.
  • TREX1 inhibition represents a promising therapeutic strategy for chemoresistant SCLC, particularly for "immunologically" cold tumors.

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