Polymerase θ inhibition steps on the cGAS pedal
Chelsea M. Smith, Gaorav P. Gupta
Chelsea M. Smith, Gaorav P. Gupta
Published June 1, 2023
Citation Information: J Clin Invest. 2023;133(11):e170660. https://doi.org/10.1172/JCI170660.
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Commentary

Polymerase θ inhibition steps on the cGAS pedal

Abstract

Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by mediating error-prone double-stranded break (DSB) repair and facilitating resistance against poly-ADP ribose polymerase inhibitor treatment. In this issue of the JCI, Oh, Wang, et al. report on the impact of Pol θ inhibition on activation of antitumor immunity. The authors used pancreatic ductal adenocarcinoma (PDAC) cell and mouse models characterized by HR-associated gene alterations and POLQ overexpression. POLQ knockdown showed synthetic lethality in combination with gene mutations involving DNA repair, including BRCA1, BRCA2, and ATM. Notably, Pol θ deficiency or inhibition suppressed tumor growth, increased the accumulation of unrepaired DNA damage, and enhanced T cell infiltration via the cGAS/STING pathway. These findings suggest a broader scope for Pol θ inhibition in HR-deficient cancers.

Authors

Chelsea M. Smith, Gaorav P. Gupta

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Figure 1

Pol θ inhibition stimulates cGAS/STING to promote T cell-directed anti-tumor immunity.

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Pol θ inhibition stimulates cGAS/STING to promote T cell-directed anti-t...
BRCA2-/- PDAC tumor cells compensate for the loss of HR by upregulating Pol θ, which mediates TMEJ and is essential for repairing DSBs. Inhibition of Pol θ results in accumulation of cGAS-positive micronuclei and STING activation. The cGAS/STING pathway activates TBK1 and IRF3 via phosphorylation, initiating Type I IFN production and release. Subsequent increases in CD4+ and CD8+ T cell infiltration with decreasing immunosuppressive M2-like TAMs result in suppression of tumor growth.