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Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma
| Content Provider | Semantic Scholar |
|---|---|
| Author | Wei, B. Michael, Helen Thompson Halsey, Charles H. C. Peer, Cody J. Adhikari, Amit S. Dwyer, Jennifer E. Hoover, Shelley K. Meskini, Rajaa El Kozlov, Sergei Ivanovich Ohler, Zoe Weaver Figg, William. D. Merlino, Glenn Simpson, Robert Mark |
| Copyright Year | 2016 |
| Abstract | Human mucosal melanoma (MM), an uncommon, aggressive and diverse subtype, shares characteristics with spontaneous MM in dogs. Although BRAF and N-RAS mutations are uncommon in MM in both species, the majority of human and canine MM evaluated exhibited RAS/ERK and/or PI3K/mTOR signaling pathway activation. Canine MM cell lines, with varying ERK and AKT/mTOR activation levels reflective of naturally occurring differences in dogs, were sensitive to the MEK inhibitor GSK1120212 and dual PI3K/mTOR inhibitor NVP-BEZ235. The two-drug combination synergistically decreased cell survival in association with caspase 3/7 activation, as well as altered expression of cell cycle regulatory proteins and Bcl-2 family proteins. In combination, the two drugs targeted their respective signaling pathways, potentiating reduction of pathway mediators p-ERK, p-AKT, p-S6, and 4E-BP1 in vitro, and in association with significantly inhibited solid tumor growth in MM xenografts in mice. These findings provide evidence of synergistic therapeutic efficacy when simultaneously targeting multiple mediators in melanoma with Ras/ERK and PI3K/mTOR pathway activation. |
| Starting Page | 643 |
| Ending Page | 655 |
| Page Count | 13 |
| File Format | PDF HTM / HTML |
| PubMed reference number | 27463366v1 |
| Alternate Webpage(s) | https://doi.org/10.1111/pcmr.12512 |
| DOI | 10.1111/pcmr.12512 |
| Journal | Pigment cell & melanoma research |
| Volume Number | 29 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | CELF Proteins Canine Melanoma Canis familiaris Cell Cycle Proteins Cell Survival Cultured Cell Line Drug Combinations Dual FRAP1 protein, human GSK 1120212 MAPK-ERK Kinases Mucosal Melanoma Mucous Membrane Mutation NVP BEZ235 Neoplasms Nevirapine Proto-Oncogene Proteins c-akt Signal Transduction Pathways Xenograft procedure cellular targeting mTOR Inhibitor solid tumor |
| Content Type | Text |
| Resource Type | Article |
