Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF

By Rizwan Haq, Jonathan Shoag, Pedro Andreu-Pérez, S. Yokoyama, Hannah E. Edelman, Glenn C. Rowe, Dennie T. Frederick, Aeron D. Hurley, Abhinav Nellore, A. Kung and 5 more. Cancer Cell, 2013

781 citations recorded by the source corpus.

Summary Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecule inhibitors leads to cell cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1α, and decreased oxidative metabolism. Conversely, treatment of BRAF mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e04bfa1d3a403227bcfc21ef09dadb3bcd915486

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In Cancer Research

1. Michael Pollak

In Molecular Biology

1. Michael Pollak
2. B. Viollet

In Oncology

1. D. Thommen
2. Ton N. Schumacher
3. K. Flaherty
4. Michael Pollak

Citations in the corpus

• Toward Minimal Residual Disease-Directed Therapy in Melanoma. (2018, positive): “Consistently, enhanced MITF expression has been linked to innate/intrinsic resistance (Gopal et al., 2014; Haq et al., 2013a, 2013b; Ji et al., 2015; Johannessen et al., 2013; Müller et al., 2014; Smith et al., 2013; Van Allen et al., 2014; Wellbrock and Arozarena, 2015).”
• Metformin: from mechanisms of action to therapies. (2014, background): “uated, resulting in enhanced antineoplastic activity of the kinase inhibitor (Haq et al., 2013).”
• T Cell Dysfunction in Cancer (2018, background): “In addition, BRAF mutations lead to constitutive activation of the MEK-MAPK pathway, thereby suppressing OXPHOS and enhancing glycolysis (Hall et al., 2013; Haq et al., 2013).”