ABCC10-mediated cGAMP efflux drives cancer cell radiotherapy resistance

TL;DR

This study identifies ABCC10 as a key protein that helps cancer cells resist radiotherapy by removing a signaling molecule called cGAMP.

Contribution

The study reveals ABCC10 as a novel efflux transporter of cGAMP involved in radiotherapy resistance.

Findings

ABCC10 exports cGAMP in an ATP-dependent manner, reducing DNA damage and ROS in cancer cells.

ABCC10 suppresses the STING-TBK1-IRF3 signaling pathway, contributing to radiotherapy resistance.

Combining radiotherapy with an ABCC10 inhibitor synergistically inhibits tumor growth in vivo.

Abstract

Although radiotherapy (RT) is used in more than 50% of cancer patients, the intrinsic radioresistance of cancer cells, characterized by metabolic adaptation, significantly limits its clinical efficacy. However, the mechanisms underlying RT resistance (RTR) remain incompletely understood. In this study, we used high-throughput metabolic CRISPR library screening and identified ABCC10 as a novel molecular contributor to RTR. Functional assays, including vesicle transport, molecular docking, and an enzyme-linked immunosorbent assay, confirmed that the R545 site of ABCC10 binds to and effluxes 2′3′-cyclic GMP–AMP (cGAMP) in an ATP-dependent manner. Mechanistically, RNA transcriptomics, along with overexpression and silencing experiments, demonstrated that ABCC10-mediated export of cGAMP suppresses the STING-TBK1-IRF3 signaling pathway. This efflux reduces RT-induced intercellular accumulation of reactive oxygen species and DNA damage. In vivo, a combination of RT and nilotinib, a potential ABCC10 inhibitor, synergistically inhibited tumor growth. In summary, we identified ABCC10 as a novel exporter of cGAMP in RTR. Our results highlight its potential role as a biomarker for predicting RT response and as a therapeutic target for overcoming RTR.

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