TY - JOUR
T1 - The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma
AU - Giricz, Orsi
AU - Mo, Yongkai
AU - Dahlman, Kimberly B.
AU - Cotto-Rios, Xiomaris M.
AU - Vardabasso, Chiara
AU - Nguyen, Hoa
AU - Matusow, Bernice
AU - Bartenstein, Matthias
AU - Polishchuk, Veronika
AU - Johnson, Douglas B.
AU - Bhagat, Tushar D.
AU - Shellooe, Rafe
AU - Burton, Elizabeth
AU - Tsai, James
AU - Zhang, Chao
AU - Habets, Gaston
AU - Greally, John M.
AU - Yu, Yiting
AU - Kenny, Paraic A.
AU - Fields, Gregg B.
AU - Pradhan, Kith
AU - Stanley, E. Richard
AU - Bernstein, Emily
AU - Bollag, Gideon
AU - Gavathiotis, Evripidis
AU - West, Brian L.
AU - Sosman, Jeffrey A.
AU - Verma, Amit K.
N1 - Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/7/25
Y1 - 2018/7/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062297982&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062297982&partnerID=8YFLogxK
U2 - 10.1172/JCI.INSIGHT.120422
DO - 10.1172/JCI.INSIGHT.120422
M3 - Article
C2 - 30046005
AN - SCOPUS:85062297982
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 14
M1 - e120422
ER -