Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Singleton, Katherine R.; Crawford, Lorin; Tsu, Elizabeth; Manchester, Haley E.; Maertens, Ophélia; Liu, Xiaojing; Liberti, Maria V.; Magpusao, Anniefer N.; Stein, Elizabeth M.; Tingley, Jennifer P.; Frederick, Dennie T.; Boland, Genevieve M.; Flaherty, Keith T.; McCall, Shannon J.; Krepler, Clemens; Sproesser, Katrin; Herlyn, Meenhard; Adams, Drew J.; Locasale, Jason W.; Cichowski, Karen; Mukherjee, Sayan; Wood, Kris C.

doi:10.2139/ssrn.3155589

SSRN Journal

2018

DOI: 10.2139/ssrn.3155589

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Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Katherine R. Singleton

Lorin Crawford

Elizabeth Tsu

et al.

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“…[16][17][18][19][20] Resistance to BRAFi seems to be accompanied by precise metabolic changes as well: higher reliance on oxidative phosphorylation, [21][22][23][24] glutamine dependency 21,25,26 and up-regulated serine metabolism. Apart from a small subset of melanomas, BRAF mutations are associated with increased glycolysis and attenuated oxidative phosphorylation, and such balance is reversed upon treatment with BRAFi.…”

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Metabolic imaging using hyperpolarized ¹³C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

Acciardo

Mignion

Lacomblez

et al. 2019

J Cellular Molecular Medi

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Nearly all melanoma patients with a BRAF‐activating mutation will develop resistance after an initial clinical benefit from BRAF inhibition (BRAFi). The aim of this work is to evaluate whether metabolic imaging using hyperpolarized (HP) 13C pyruvate can serve as a metabolic marker of early response to BRAFi in melanoma, by exploiting the metabolic effects of BRAFi. Mice bearing human melanoma xenografts were treated with the BRAFi vemurafenib or vehicle. In vivo HP 13C magnetic resonance spectroscopy was performed at baseline and 24 hours after treatment to evaluate changes in pyruvate‐to‐lactate conversion. Oxygen partial pressure was measured via electron paramagnetic resonance oximetry. Ex vivo qRT‐PCR, immunohistochemistry and WB analysis were performed on tumour samples collected at the same time‐points selected for in vivo experiments. Similar approaches were applied to evaluate the effect of BRAFi on sensitive and resistant melanoma cells in vitro, excluding the role of tumour microenvironment. BRAF inhibition induced a significant increase in the HP pyruvate‐to‐lactate conversion in vivo, followed by a reduction of hypoxia. Conversely, the conversion was inhibited in vitro, which was consistent with BRAFi‐mediated impairment of glycolysis. The paradoxical increase of pyruvate‐to‐lactate conversion in vivo suggests that such conversion is highly influenced by the tumour microenvironment.

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confidence: 99%

Metabolic imaging using hyperpolarized ¹³C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

Acciardo

Mignion

Lacomblez

et al. 2019

J Cellular Molecular Medi

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Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Cited by 1 publication

References 33 publications

Metabolic imaging using hyperpolarized ¹³C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

Metabolic imaging using hyperpolarized ¹³C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

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Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Cited by 1 publication

References 33 publications

Metabolic imaging using hyperpolarized 13C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

Metabolic imaging using hyperpolarized 13C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

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Metabolic imaging using hyperpolarized ¹³C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

Metabolic imaging using hyperpolarized ¹³C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts