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Synergistic targeted inhibition of MEK and dual PI 3K/ mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma
Author(s) -
Wei BihRong,
Michael Helen T.,
Halsey Charles H.C.,
Peer Cody J.,
Adhikari Amit,
Dwyer Jennifer E.,
Hoover Shelley B.,
El Meskini Rajaa,
Kozlov Serguei,
Weaver Ohler Zoe,
Figg William. D.,
Merlino Glenn,
Simpson R. Mark
Publication year - 2016
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12512
Subject(s) - pi3k/akt/mtor pathway , cancer research , chemistry , melanoma , pharmacology , biology , signal transduction , biochemistry
Summary 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 PI 3K/ 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 GSK 1120212 and dual PI 3K/ mTOR inhibitor NVP ‐ BEZ 235. 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‐ BP 1 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 PI 3K/ mTOR pathway activation.