Excision repair cross complementation group 1 gene exon 3 skipping isoform presents selective cGAS-STING activation...

Platinum-based chemotherapy is widely used as a frontline therapy for lung adenocarcinoma, while its efficacy is limited by agent resistance and severe toxicity. Recently the immunotherapy represents an alternative or complement to Platinum-based chemotherapy. Interestingly, the sensitivity to platinum is known as a relevant phenotypical biomarker of valid immunotherapy due to the defects in DNA damage response (DDR) in cancer cells. The cGAS/STING pathway detects cytosolic DNA to activate innate immune response, which seems to become a bridge linking DDR and cancer immunogenicity. This study aimed to investigate the effect of ERCC1 splicing isoforms on the cGAS/STING pathway. Besides, the association of ERCC1 splicing isoforms with cGAS/STING signaling in cisplatin-treated cells was analyzed, and the modulation of PRPF8 on ERCC1 exon skipping splicing was elucidated by RNA immunoprecipitation. Finally, we also explored the potential role of an herbal extract β-elemene as chemosensitizer and activator of cGAS/STING signaling. We demonstrated that ERCC1 exon 3 inclusion was of equal importance to exon 8 and endowed ERCC1 with an elevated DNA repair activity, which was linked with cisplatin resistance and cGAS-STING suppression. Mechanistically, PRPF8 was identified to be directly interacted with modulating ERCC1 exon 3 skipping, while β-elemene was found to be involved in the activation of cGAS-STING signaling as an inhibitor of PRPF8. Our data reveal that the ERCC1 exon 3 skipping isoform is associated with DDR and the cGAS/STING innate immune pathway, which provide preclinical rationale for using alternative or complement immunotherapy in Platinum-sensitive NSCLC patients.