Oncotarget

Research Papers:

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

James L. Figarola _, Jyotsana Singhal, Sharad Singhal, Jyotirmoy Kusari and Arthur Riggs

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:36945-36965. https://doi.org/10.18632/oncotarget.26421

Metrics: PDF 1732 views  |   HTML 2397 views  |   ?  


Abstract

James L. Figarola1, Jyotsana Singhal1, Sharad Singhal2, Jyotirmoy Kusari1 and Arthur Riggs1

1Division of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA

2Department of Medical Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA

Correspondence to:

James L. Figarola, email: [email protected]

Keywords: BRAF; MAPK; mitochondria; uncoupler; xenograft

Received: August 31, 2018    Accepted: November 16, 2018    Published: December 11, 2018

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 26421