Combinatorial therapy to target melanoma resistant to immune checkpoint blockade

Immune checkpoint blockade (ICB) has revolutionized melanoma therapy, but drug resistance represents a significant limitation. Here we utilize a platform incorporating transcriptomic profiling, high-throughput drug screening (HTDS) and murine models to demonstrate the pre-clinical efficacy of cobimetinib and regorafenib (termed Cobi+Reg) for ICB-resistant melanoma. RNA-Sequencing (RNA-Seq) analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. HTDS targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft (PDX) models. Cobi+Reg emerged as the most promising regimen, with efficacy against distinct molecular melanoma subtypes and following progression on ICB in immunocompetent models. RNA-Seq analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either treatment in vivo. This analytical platform has identified several effective combinations, presenting Cobi+Reg as a rational therapeutic strategy either following resistance to or combined with ICB for advanced melanoma.