Targeting Glutamatergic Signaling and the PI3 Kinase Pathway to Halt Melanoma Progression.
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.
Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI, USA; Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Stephen A
SA
Rosenberg
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Scot A
SA
Niglio
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Negar
N
Salehomoum
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Joseph L-K
JL
Chan
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Byeong-Seon
BS
Jeong
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Yu
Y
Wen
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Jiadong
J
Li
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jami
J
Fukui
Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, NJ, USA.
Suzie
S
Chen
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Seung-Shick
SS
Shin
Department of Surgery, Division of Surgical Oncology, Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Electronic address: goydosjs@cinj.rutgers.edu.
James S
JS
Goydos