The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma
Rachel Ramsdale, Robert N Jorissen, Frederic Z Li, Sheren Al-Obaidi, Teresa Ward, Karen E Sheppard, Patricia E Bukczynska, Richard J Young, Samantha E Boyle, Mark Shackleton, Gideon Bollag, Georgina V Long, Eugene Tulchinsky, Helen Rizos, Richard B Pearson, Grant A McArthur, Amardeep S Dhillon, Petranel T Ferrao
SCIENCE SIGNALING | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2015
Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mitogen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAF(V600)-mutant melanoma cell lines was associated with high abundance of c-JUN and characteristics of a mesenchymal-like phenotype. Early drug adaptation in drug-sensitive cell lines grown in culture or as xenografts, and in patient samples during therapy, was consistently characterized by down-regulation of SPROUTY4 (a negative feedback regulator of receptor tyrosine kinases and the BRAF-MEK signaling pathwa..View full abstract
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Awarded by National Health and Medical Research Council of Australia
This project was supported by funding to P.T.F. from the Peter MacCallum Cancer Foundation, the CASS Foundation, and the National Health and Medical Research Council of Australia (NHMRC 1042980). F.Z.L. receives scholarships from the China Scholarships Council and Cancer Therapeutics CRC. M.S. was supported by the Australian National Health and Medical Research Council, Pfizer Australia, and the Victorian Endowment for Science, Knowledge and Innovation.