Our group has previously reported that the majority of human
melanomas (>60%) express the
metabotropic glutamate receptor 1 (GRM1) and that the
glutamate release inhibitor
riluzole, a
drug currently used to treat
amyotrophic lateral sclerosis, can induce apoptosis in GRM1-expressing
melanoma cells. Our group previously reported that in vitro
riluzole treatment reduces cell growth in three-dimensional (3D) soft
agar colony assays by 80% in cells with wildtype
phosphoinositide 3-kinase (PI3K) pathway activation. However,
melanoma cell lines harboring constitutive activating mutations of the PI3K pathway (PTEN and NRAS mutations) showed only a 35% to 40% decrease in colony formation in soft
agar in the presence of
riluzole. In this study, we have continued our preclinical studies of
riluzole and its effect on
melanoma cells alone and in combination with inhibitors of the
PI3 kinase pathway: the AKT inhibitor,
API-2, and the
mammalian target of rapamycin (mTOR) inhibitor,
rapamycin. We modeled these combinatorial
therapies on various
melanoma cell lines in 3D and 2D systems and in vivo.
Riluzole combined with mTOR inhibition is more effective at halting
melanoma anchorage-independent growth and xenograft
tumor progression than either agent alone. PI3K signaling changes associated with this combinatorial treatment shows that 3D (nanoculture) modeling of cell signaling more closely resembles in vivo signaling than monolayer models.
Riluzole combined with mTOR inhibition is effective at halting
tumor cell progression independent of BRAF mutational status. This makes this combinatorial
therapy a potentially viable alternative for metastatic
melanoma patients who are BRAF WT and are therefore ineligible for
vemurafenib therapy.