ESTRO 2024 - Abstract Book

S5350

Radiobiology - Tumour biology

ESTRO 2024

However, the specific metabolic pathway that forms the core reason for radiotherapy resistance still requires further exploration. Our objective is to unveil unknown key metabolic radioresistant molecules and investigate their regulatory mechanisms to overcome radioresistance.

Material/Methods:

A CRISPR library screening enriched with metabolic genes was employed to find ABCC10 as a key radioresistant gene. CRISPR-Cas9 mediated gene editing technology was utilized for constructing knockout as well as overexpression cell lines. A series of experiments were conducted to validate that ABCC10 mediates radiotherapy resistance. RNA-seq and pathway enrichment analysis were performed to explore downstreaming pathway of ABCC10. We then executed western blot and cGAMP ELISA assay to detect signaling activity. Subcutaneous and orthotopic tumor model were established to evaluate the efficacy of ABCC10 inhibitor in sensitizing radiotherapy.

Results:

Our investigation revealed ABCC10 as an intrinsic and pivotal regulatory molecule within tumor cells. We discern that ABCC10 can mediate the efflux of cGAMP, thereby suppressing the phosphorylation activation of STING and its downstream pathways under radiotherapeutic conditions, resulting in diminished reactive oxygen species (ROS) generation and DNA damage. In concordance with these findings, genetic or pharmacological inhibition of ABCC10 induces intracellular accumulation of cGAMP, consequently further activating the STING-TBK1-IRF3 signaling pathway. We also demonstrate that an efficacious inhibitor of ABCC10, nilotinib, can sensitize radiotherapy outcomes by augmenting STING-mediated DNA damage in vitro and in vivo.

Conclusion:

These results underscore a role for ABCC10 beyond its canonical function in drug resistance resulting from the efflux of chemotherapeutic agents and identify ABCC10-mediated cGAMP export as a key regulatory mechanism limiting cell-intrinsic activation of STING and STING-dependent ROS generation and DNA damage in radiotherapy. Furthermore, we verified that the inhibitor of ABCC10 exhibits a notable radiosensitizing effect, offering a novel strategy to overcome radiotherapy resistance.

Keywords: ABCC10, CGAS-STING, radiotherapy

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