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JCI Insight. 2018 Jul 25;3(14). pii: 120422. doi: 10.1172/jci.insight.120422. [Epub ahead of print]

The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma.

Author information

1
Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
2
Vanderbilt University, Nashville, Tennessee, USA.
3
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
4
Departments of Oncological Sciences & Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
Plexxikon, Berkeley, California, USA.
6
Department of Genetics and.
7
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
8
Department of Chemistry and Biochemistry, Florida Atlantic University, Florida, USA.

Abstract

Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples. CSF1R was particularly elevated in melanomas with BRAF and other MAPK activating mutations. Furthermore, rebound ERK activation after BRAF inhibition was associated with RUNX1-mediated further upregulation of CSF-1R and its ligand IL-34. Importantly, increased CSF-1R and IL-34 overexpression were detected in an independent cohort of resistant melanomas. Inhibition of CSF-1R kinase or decreased CSF-1R expression by RNAi reduced 3-D growth and invasiveness of melanoma cells. Coinhibition of CSF-1R and BRAF resulted in synergistic efficacy in vivo. To our knowledge, our data unveil a previously unknown role for the autocrine-regulated CSF-1R in BRAF V600E resistance and provide a preclinical rationale for targeting this pathway in melanoma.

KEYWORDS:

Melanoma; Oncology

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