Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma

Abstract

Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due to BRAF mutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased βNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by 1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.

Assessment of Metabolic Imaging Biomarkers for MEK Inhibition Therapy Response in Melanoma

“…Published research, including ours, shows that magnetic resonance spectroscopy (MRS) is a noninvasive avenue for monitoring metabolic changes in melanoma models following diverse anticancer treatments [10,11]. We demonstrated that MRS discerns significant changes in metabolic signatures in successfully treated melanoma models with dabrafenib, a BRAF inhibitor, showcasing early therapy-related changes in metabolomics, pH, and bioenergetics [10]. This elucidation underscores the potential of MRS in delineating early-treatment metabolic responses to targeted therapies.…”

“…In addition, the comparison of slopes for pHe of DB-1 between untreated (m = -0.020) and trametinib treated (m = 0.010) was statistically significant (p = 0.02). Published research, including ours, shows that magnetic resonance spectroscopy (MRS) is a noninvasive avenue for monitoring metabolic changes in melanoma models following diverse anticancer treatments [10,11]. We demonstrated that MRS discerns significant changes in metabolic signatures in successfully treated melanoma models with dabrafenib, a BRAF inhibitor, showcasing early therapy-related changes in metabolomics, pH, and bioenergetics [10].…”

“…The reagents used for cell cultures and biochemical analyses, including 3aminopropylphosphonate (3-APP) and their sources, are listed in our previous study [10]. Trametinib was obtained from LC Laboratories (Woburn, MA, USA).…”

“…DB-1 (Accession No: CVCL_D902) and WM983B (Accession No: CVCL_6809) cells were cultured in MEM-α media supplemented with glucose, glutamine, antibiotics, MEM NEAA, and FBS. More detailed culturing conditions are described elsewhere [10].…”

“…Melanoma treatment, incorporating surgery, chemotherapy, immunotherapy, and radiotherapy, faces challenges due to melanoma resistance, primarily attributed to melanin production. Recent focus has been on targeting the mitogen-activated protein kinases (MAPK) pathway to overcome resistance and improve therapeutic outcomes [9,10]. Inhibiting the BRAF or MEK portions of the MAPK pathway exerts primarily cytostatic effects compared to chemotherapy.…”