Melanoma is the most lethal human
skin cancer. If metastatic, it becomes very aggressive and resistant to standard modalities of anticancer treatment. During the last 10 years, several therapeutic strategies have been tested including the use of single and combined small drugs. Experimental results indicate that RAS and PI3K pathways are important for the development and maintenance of
melanoma. In this study, we assessed the in vitro and in vivo inhibition potential of
PI-103, a PI3K (p110alpha)/mTOR inhibitor and
sorafenib, a BRAF inhibitor, as single agents and in combination in primary
melanoma cell lines. Although
PI-103 and
sorafenib inhibited
melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway appeared to be more effective. The combination of the two agents in in vitro showed a synergistic effect inhibiting RAS and PI3K pathways in a cell line dependent manner. However, no cooperative effect was observed in blocking in vivo
tumor growth in immunocompetent mice. In contrary to the expected, the data indicate that
PI-103 induced immunosuppression promoting in vivo
tumor growth and inhibiting apoptosis. Furthermore, in vitro studies examining the effects of the PI3K/mTOR inhibitor in
tumor derived cell lines indicated that
PI-103 induced the anti-apoptotic BH3 family
proteins Mcl1, Bcl2 and Bcl(xL) favoring, the in vitro survival of
sorafenib treated
melanoma cells. These data certainly makes an argument for investigating unexpected effects of rational
drug combinations on immunocompetent animal models prior to conducting clinical studies.