Abstract
BRAF mutations are detected in >50% of all melanomas. These mutations impair the LKB1-AMPK signaling, an important metabolic pathway associated with cell growth, proliferation and survival. Melanoma patients with BRAF mutations are usually treated with BRAF inhibitors such as vemurafenib, but responses are short-lived as drug resistant tumors metabolically switch to mitochondrial oxidative phosphorylation (OXPHOS) to escape metabolic stress-induced BRAF inhibition. Additionally, a large subset of melanoma utilizes OXPHOS in their metabolism, which can confer de novo resistance to BRAF inhibitors. Therefore, uncoupling of OXPHOS to perturb energy homeostasis and to indirectly stimulate AMPK could be a novel treatment for melanoma and to overcome intrinsic and acquired resistance to BRAF inhibitors. Here, we investigated the effects of SR4 and niclosamide, two small molecule mitochondria uncouplers, on the growth and proliferation of treatment-naïve and vemurafenib-resistant melanomas in vitro and in vivo. SR4 and niclosamide inhibited melanoma proliferation irrespective of BRAF/NRAS status. Melanomas with greater OXPHOS phenotype (higher OCR/ECAR), with LKB1 mutation, or with acquired resistance to vemurafenib displayed greater sensitivity to both uncouplers. More importantly, SR4 and niclosamide inhibited tumor growth in both treatment-naïve and vemurafenib-resistant xenograft mice models. Mechanistic studies indicate both uncouplers induced energetic stress, modulated the AMPK-mTOR pathway, and promoted apoptosis without affecting MEK-ERK MAPK signaling. These results suggest that uncouplers such as SR4 and niclosamide may be useful as first line treatment against melanoma regardless of BRAF/NRAS status, and as an adjuvant therapy for patients failing MAPK inhibitors.
Highlights
Melanoma is the deadliest form of skin cancer and its incidence continues to increase worldwide
SR4 and niclosamide inhibited tumor growth in both treatmentnaïve and vemurafenib-resistant xenograft mice models. Mechanistic studies indicate both uncouplers induced energetic stress, modulated the AMPK-mTOR pathway, and promoted apoptosis without affecting MEK-ERK MAPK signaling. These results suggest that uncouplers such as SR4 and niclosamide may be useful as first line treatment against melanoma regardless of BRAF/NRAS status, and as an adjuvant therapy for patients failing MAPK inhibitors
We investigated the metabolic effects of SR4 and niclosamide (Figure 1A), two small molecules that were recently identified as mitochondria uncouplers, against treatment naïve wild type, BRAFV600E and NRAS mutant, and BRAF inhibitor-resistant melanomas
Summary
Melanoma is the deadliest form of skin cancer and its incidence continues to increase worldwide. All the mutations occur within the kinase domain, and the specific V600E missense valine to glutamic acid mutation accounts for approximately 80–90% of BRAF mutations [2, 3] This mutation leads to a conformational change resulting in constitutive activation of BRAF, and of the MEK/ERK. Mechanisms of acquired resistance to BRAF inhibition can be subdivided in two groups: MAPK-dependent and MAPK-independent The former is primarily due to MEK/ERK reactivation resulting from amplification of BRAF, BRAF splicing, NRAS mutation, MEK mutation and loss of NF1, while the latter resistance mechanisms include up-regulated receptor tyrosine kinases (RTKS), activating mutations in AKT and loss of function mutations in PTEN and overexpression of COT [7,8]. Despite the recent success in the development of targeted therapies for melanoma, the problem of drug resistance and the rapidly rising incidence and morbidity rate of melanoma underscore the urgency to better understand its pathogenesis and identify potential therapeutic targets and treatment strategies
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