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.
Document Type
Article
Publication Date
8-10-2017
Digital Object Identifier (DOI)
https://doi.org/10.1038/onc.2017.76
Funding Information
This work was supported by NIH grant R01CA166499 to R.P. C.W. is funded by NIH/NCI, but this work was not supported by his grants.
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).
Related Content
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Repository Citation
Jain, Aditi; Tripathi, Rakshamani; Turpin, Courtney P.; Wang, Chi; and Plattner, Rina, "Abl Kinase Regulation by BRAF/ERK and Cooperation with Akt in Melanoma" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 93.
https://uknowledge.uky.edu/pharmacol_facpub/93
Supplementary Materials
onc201776x2.doc (44 kB)
Supplementary Figure Legends
onc201776x3.ppt (4428 kB)
Supplementary Figures
onc201776x4.doc (23 kB)
Supplementary Table Legend
onc201776x5.doc (55 kB)
Supplementary Table 1
Notes/Citation Information
Published in Oncogene, v. 36, issue 32, p. 4585-4596.
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
The copyright holder has granted the permission for posting the article here.
This is a post-peer-review, pre-copyedit version of an article published in Oncogene. The final authenticated version is available online at: https://doi.org/10.1038/onc.2017.76.