title: Abl kinase regulation by BRAF/ERK and cooperation with Akt in melanoma.
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 BRAFV600Eand 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 BRAFV600Ehas 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.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, KY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, KY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, KY, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Turpin
authors.affiliation: Department of Biostatistics and Markey Cancer Center, University of Kentucky School of Medicine, Lexington, KY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky School of Medicine, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky School of Medicine, Lexington, KY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Plattner
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099254:Organic Cation Transporter 3
chemical_list: D027701:Organic Cation Transport Proteins; D051059:PTEN Phosphohydrolase; D017027:Protein Tyrosine Phosphatases; D048493:Proto-Oncogene Proteins B-raf; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000099254:Organic Cation Transporter 3; C482119:BRAF protein, human; C096335:B59 protein, human; C494929:PTEN protein, human; C498826:nilotinib