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. Few effective therapeutic options exist following progression on ICB in melanoma. Here, the biology of ICB-resistant melanoma was exploited in order to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.