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Abl kinase regulation by BRAF/ERK and cooperation with Akt in melanoma

Oncogene volume 36, pages 4585–4596 (2017)Cite this article

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Abstract

The melanoma incidence continues to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance. In particular, melanomas harboring BRAFV600E and PTEN mutations often are resistant to current therapies, including BRAF inhibitors (BRAFi) and immune checkpoint inhibitors. Abl kinases (Abl/Arg) are activated in melanomas and drive progression; however, their mechanism of activation has not been established. Here we elucidate a novel link between BRAFV600E/ERK signaling and Abl kinases. We demonstrate that BRAFV600E/ERK play a critical role in binding, phosphorylating and regulating Abl localization and Abl/Arg activation by Src family kinases. Importantly, Abl/Arg activation downstream of BRAFV600E has functional and biological significance, driving proliferation, invasion, as well as switch in epithelial–mesenchymal–transition transcription factor expression, which is known to be critical for melanoma cells to shift between differentiated and invasive states. Finally, we describe findings of high translational significance by demonstrating that Abl/Arg cooperate with PI3K/Akt/PTEN, a parallel pathway that is associated with intrinsic resistance to BRAFi and immunotherapy, as Abl/Arg and Akt inhibitors cooperate to prevent viability, cell cycle progression and in vivo growth of melanomas harboring mutant BRAF/PTEN. Thus, these data not only provide mechanistic insight into Abl/Arg regulation during melanoma development, but also pave the way for the development of new strategies for treating patients with melanomas harboring mutant BRAF/PTEN, which often are refractory to current therapies.

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Acknowledgements

This work was supported by the Markey Cancer Center Flow Cytometry, Biospecimen and Tissue Procurement, and Biostatistics Shared Resources and the Research Communication Office (P30CA177558). We thank Drs D’Orazio and Kyprianou for critically reading the manuscript. This work was supported by NIH Grant R01CA166499 to RP.

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Authors and Affiliations

  1. Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, KY, USA

    A Jain, R Tripathi, C P Turpin & R Plattner

  2. Department of Biostatistics and Markey Cancer Center, University of Kentucky School of Medicine, Lexington, KY, USA

    C Wang

  3. Department of Toxicology and Cancer Biology, University of Kentucky School of Medicine, Lexington, KY, USA

    R Plattner

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Correspondence to R Plattner.

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This work was supported by an NIH/NCI grant to RP. CW is funded by NIH/NCI, but this work was not supported by his grants. The remaining authors declare no potential conflict of interest.

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Jain, A., Tripathi, R., Turpin, C. et al. Abl kinase regulation by BRAF/ERK and cooperation with Akt in melanoma. Oncogene 36, 4585–4596 (2017). https://doi.org/10.1038/onc.2017.76

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