Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-na ïve and vemurafenib-resistant melanomas.

Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-naïve and vemurafenib-resistant melanomas. Oncotarget. 2018 Dec 11;9(97):36945-36965 Authors: Figarola JL, Singhal J, Singhal S, Kusari J, Riggs A 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 L...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research