Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma

Abstract

Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Pre-clinical studies suggest that ERK inhibitors are likely to provide benefit, albeit with limited efficacy as single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. Combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mTOR signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate (OCR), indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional co-activator PGC1α. In contrast, co-treatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the OCR. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.

Treatment of Pancreatic Cancer Patient–Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin

“…A recent report showed that phenformin, but not metformin, strongly reduces melanoma cell viability, growth, and abrogates melanoma cell invasion (45). Furthermore, phenformin has been reported to enhance the therapeutic efficacy ofBRAF (V600E) and ERK inhibitors in melanoma (46, 47). The encouraging antitumor efficacy of phenformin in our study, in the context of the disappointing efficacy of metformin in a recent pancreatic cancer clinical trial, suggests that phenformin merits clinical investigation as an anticancer agent for the treatment of pancreatic cancer.…”

Tackling malignant melanoma epigenetically: histone lysine methylation

“…Treatment of melanoma tumors with MAPK inhibitors increases the H3K4 demethylase JARID1B-positive subpopulation of melanoma cells [ 15 ]. These cells are slow-cycling and treatment-resistant.…”

Translational and HIF11-Dependent Metabolic Reprograming Underpin Oncometabolome Plasticity and Synergy Between Oncogenic Kinase Inhibitors and Biguanides

“…For instance, metformin has been shown to increase the effects of anti-HER2 monoclonal antibody trastuzumab (Herceptin) by suppressing self-renewal and proliferation of cancer stem/progenitor cells in HER2-positive carcinomas (Vazquez-Martin et al, 2011). Similarly, phenformin potentiates the effects of BRAF and ERK inhibitors in BRAF(V600E) and NF1-mutant melanoma cells, respectively, through the selective targeting of JARID1B-expressing subpopulation of cells (Trousil et al, 2017;Yuan et al, 2013). Although that these findings are presently being studied in clinical trials in which biguanides are combined with KIs, the underlying mechanisms and generality of the effects of such combinations are incompletely described.…”

“…Combining KIs and phenformin has been shown to be effective in melanoma cells (Trousil et al, 2017;Yuan et al, 2013). We therefore first sought to establish the universality of these findings by combining clinically used KIs and phenformin in cancer cell lines of different origin that harbor diverse activated forms of oncogenic kinases.…”

“…As KIs used in the clinic also reduce glycolysis (Pollak, 2013;Zhao et al, 2011), this is an attractive rationale for combining these drugs with biguanides. Indeed, biguanides potentiate effects of BRAF and ERK inhibitors in melanoma (Trousil et al, 2017;Yuan et al, 2013). However, the metabolic and signaling pathways that mediate anti-neoplastic effects of KI and biguanide combinations are largely unknown.…”