Increased IRF9–STAT2 Signaling Leads to Adaptive Resistance toward Targeted Therapy in Melanoma by Restraining GSDME-Dependent Pyroptosis

Melanoma is the leading cause of cutaneous malignancy death. BRAF inhibitors (BRAFis) have been developed as target therapies because nearly half of patients with melanoma have activating alterations in the BRAF oncogene. However, the fast-developed resistance to BRAFis limits their treatment efficacy. Understanding the molecular mechanism of resistance is vital to increase the success of clinical treatment. We searched three datasets (GSE42872, GSE52882, and GSE106321) from the Gene Expression Omnibus database, which analyzed the mRNA expression profile of melanoma cells under BRAFis treatment, and the differentially expressed genes were identified. Among all the differentially expressed genes, the increased expression of IRF9 and STAT2 was prominent and verified to be upregulated in BRAFis-treated melanoma cells. Furthermore, IRF9 or STAT2 overexpression led to less sensitivity, whereas IRF9 or STAT2 knockdown increased sensitivity to BRAFis treatment. In a subcutaneous xenograft tumor model, we showed that IRF9 or STAT2 overexpression slowed BRAFis-induced tumor shrinking, but IRF9 or STAT2 knockdown led to BRAFis-induced tumor shrinking more quickly. Interestingly, we discovered that IRF9–STAT2 signaling controlled GSDME-dependent pyroptosis by restoring GSDME transcription. These results suggest that targeting IRF9/STAT2 may lead to more promising effective treatments to prevent melanoma resistance to BRAFis by inducing pyroptosis. Melanoma is the leading cause of cutaneous malignancy death. BRAF inhibitors (BRAFis) have been developed as target therapies because nearly half of patients with melanoma have activating alterations in the BRAF oncogene. However, the fast-developed resistance to BRAFis limits their treatment efficacy. Understanding the molecular mechanism of resistance is vital to increase the success of clinical treatment. We searched three datasets (GSE42872, GSE52882, and GSE106321) from the Gene Expression Omnibus database, which analyzed the mRNA expression profile of melanoma cells under BRAFis treatment, and the differentially expressed genes were identified. Among all the differentially expressed genes, the increased expression of IRF9 and STAT2 was prominent and verified to be upregulated in BRAFis-treated melanoma cells. Furthermore, IRF9 or STAT2 overexpression led to less sensitivity, whereas IRF9 or STAT2 knockdown increased sensitivity to BRAFis treatment. In a subcutaneous xenograft tumor model, we showed that IRF9 or STAT2 overexpression slowed BRAFis-induced tumor shrinking, but IRF9 or STAT2 knockdown led to BRAFis-induced tumor shrinking more quickly. Interestingly, we discovered that IRF9–STAT2 signaling controlled GSDME-dependent pyroptosis by restoring GSDME transcription. These results suggest that targeting IRF9/STAT2 may lead to more promising effective treatments to prevent melanoma resistance to BRAFis by inducing pyroptosis.