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Mutant RB1 enhances therapeutic efficacy of PARPis in lung adenocarcinoma by triggering the cGAS/STING pathway

Qi Dong1,2, Tong Yu3,4, Bo Chen1

  • 1Department of Systems Biology, College of Bioinformatics Science and Technology, and.

JCI Insight
|November 8, 2023
PubMed

Insights

Retinoblastoma gene (RB1) mutations sensitize lung adenocarcinoma (LUAD) to Poly (ADP-ribose) polymerase inhibitors (PARPis). This occurs via the cGAS/STING pathway, promoting immune cell infiltration and reducing tumor growth, suggesting a new therapeutic strategy for LUAD.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPis) are established cancer therapeutics.
  • Their efficacy in lung adenocarcinoma (LUAD) and the role of retinoblastoma gene (RB1) mutations remain unclear.

Purpose of the Study:

  • To investigate the impact of RB1 mutations on PARPi sensitivity in LUAD.
  • To identify potential biomarkers for PARPi therapy in LUAD.

Main Methods:

  • Bioinformatic screening for PARPi-sensitive biomarkers.
  • In vitro assessment of LUAD cell line viability with PARPis.
  • Analysis of DNA damage, cGAS/STING pathway activation, and chemokine expression.
  • Xenograft experiments in RB1-deficient mice.
  • Single-cell RNA sequencing (scRNA-seq) analysis.

Main Results:

  • LUAD cell lines with mutated RB1 exhibited significantly reduced viability upon treatment with PARPis (niraparib, rucaparib, olaparib).
  • RB1 deficiency led to genomic instability, cytosolic double-stranded DNA (dsDNA) accumulation, and activation of the cGAS/STING pathway.
  • Upregulation of chemokines CCL5 and CXCL10 was observed, correlating with increased immune cell infiltration.
  • PARPi treatment reduced tumor growth in RB1-deficient xenografts.
  • scRNA-seq revealed enhanced cell-cell communication and immune-related signaling in RB1-deficient LUAD cells.

Conclusions:

  • RB1 mutations confer sensitivity to PARPis in LUAD through a synthetic lethal mechanism.
  • The cGAS/STING pathway activation and subsequent immune infiltration are key mediators of this sensitivity.
  • RB1 status may serve as a predictive biomarker for PARPi therapy in LUAD, offering a potential new therapeutic strategy.
Keywords:
Cancer immunotherapyDrug therapyGenetic instabilityGeneticsTherapeutics

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