Melanoma frequently harbors oncogenic mutations in the BRAF gene, which drives melanoma growth. Therefore, BRAF kinase inhibitors (BRAFi) are developed and approved for treating BRAF-mutant melanoma. However, the efficacy of BRAFi is limited due to acquired resistance, and in over 40% of melanoma, the causes of BRAFi resistance remain unknown. Here, using a human phospho-receptor tyrosine kinase array we identified Anaplastic Lymphoma Kinase (ALK) as a driver of acquired BRAFi resistance in melanoma. We found that ALK ligand FAM150A was necessary for ALK activation and ALK via the PI3K/AKT pathway was sufficient to confer resistance to BRAFi. ALK inhibitor (ALKi) ceritinib inhibited BRAFi-resistant melanoma in cell culture and mice. Residual BRAFi and ALKi dual resistant melanoma cells from ceritinib-treated mice were sensitive to a broad-spectrum anti-apoptotic protein inhibitor, AT101. Collectively, our results provide a framework for treating BRAF-mutant melanoma that sequentially uses different targeted therapies based on post-treatment tumor evolution.
