Identifying microbial determinants of response and resistance to targeted therapy in melanoma

Mutations in the BRAF gene occur in over half of melanoma tumors and result in constitutive signaling of the mitogen activated protein kinase (MAPK) pathway leading to enhanced cellular proliferation and survival. Treatment with MAPK pathway inhibitors targeting this genetic abnormality is associated with clinical benefit in the majority of patients with BRAF-mutant melanoma. However, relapse is almost universal. We focused on one aspect of the tumor microenvironment that remains largely unstudied in the context of acquired resistance to BRAF/MAPK pathway inhibitors, namely, the role of the host microbiome. We hypothesized that bacteria present in the tumor and gut of patients may differentially modulate responses to targeted therapy, and that through targeting these bacteria, therapeutic responses might be enhanced. We have located a small number of bacterial species that are highly enriched in the group of melanoma patients that responded to BRAF/MEK inhibitors. We are now developing a syngeneic model of tumors that can be infected with bacteria for the identification of strategies to overcome microbial-mediated resistance to targeted therapy in-vivo.