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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.

pigment cell and melanoma research

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