Integrated and Functional Genomic Approaches to Elucidate Differential Genetic Dependencies in Melanoma

Abstract

Genomic characterization of human cancers over the past decade has generated comprehensive catalogues of genetic alterations in cancer genomes. Many of these genetic events result in molecular or cellular changes that drive cancer cell phenotypes. In melanoma, a majority of tumors harbor mutations in the BRAF gene, leading to activation of the MAPK pathway and tumor initiation. The development and use of drugs that target the mutant BRAF protein and the MAPK pathway have produced significant clinical benefit in melanoma patients. In addition, recent advances in cancer immunotherapy have led to dramatic and durable responses in tumor types with high mutation rates, including melanoma. However, innate and acquired resistance to targeted therapy and immunotherapy necessitate the discovery, investigation, and pursuit of novel and orthogonal tumor dependencies for the treatment of cancer patients. In this work, we applied the analysis of functional genomic screening data and cistromic and transcriptomic experimental approaches to characterize SOX10 as a differential genetic dependency in melanoma. To identify novel and potentially actionable lineage-specific differential genetic dependencies across cancer, we performed class-based computational analyses of Project Achilles dependency data. In melanoma, known differential dependencies included BRAF and MAPK1, while SOX10 was the highest ranked novel genetic dependency. Integrative analysis with additional genomic data uncovered a gene expression-dependency relationship for SOX10 in melanoma, which we confirmed, showing that only cell lines that express SOX10 are dependent on SOX10 for cell proliferation. To further investigate SOX10 dependency in melanoma, we characterized the cistrome, the complete set of binding sites in the genome, and transcriptome of SOX10 in melanoma cell lines. The integration of these datasets enabled the determination of SOX10 target genes and downstream pathways in melanoma, including shared target genes with the well-known oncoprotein MYC. Additional analysis of SOX10 target genes by MITF expression revealed MITF class-specific SOX10 transcriptional programs in melanoma, characterized by MITF in MITF-high melanoma and FOS-JUN in MITF-low melanoma. Taken together, our studies provide new insights into the role and importance of SOX10 in melanoma biology and pave the way for the integration of large-scale datasets to identify and characterize genetic dependencies in cancer.