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iScience. 2019 Jun 28;16:453-467. doi: 10.1016/j.isci.2019.06.001. Epub 2019 Jun 8.

Anaplastic Lymphoma Kinase Confers Resistance to BRAF Kinase Inhibitors in Melanoma.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: nwajapey@uab.edu.

Abstract

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.

KEYWORDS:

Biological Sciences; Cancer; Cell Biology; Functional Aspects of Cell Biology

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