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 - Funding Information:
We thank the Albert Einstein Genomics Core, David Reynolds and Kevin Lau for help with the MassARRAY EPITYPER assay. Part of this work was supported by the Pershing Square Sohn Cancer Research Alliance and Department of Defense W81XWH-14-1-0230 to EB. The RNA in situ hybridization slides were scanned by Vera DesMarais in the Analytical Imaging Facility at Albert Einstein College of Medicine, which is funded by Cancer Center grant P30CA013330, using the 3DHistec Panoramic 250 Flash II slide scanner (funded by SIG 1S10OD019961-01).
Funding Information:
We thank the Albert Einstein Genomics Core, David Reynolds and Kevin Lau for help with the MassAR-RAY EPITYPER assay. Part of this work was supported by the Pershing Square Sohn Cancer Research Alliance and Department of Defense W81XWH-14-1-0230 to EB. The RNA in situ hybridization slides were scanned by Vera DesMarais in the Analytical Imaging Facility at Albert Einstein College of Medicine, which is funded by Cancer Center grant P30CA013330, using the 3DHistec Panoramic 250 Flash II slide scanner (funded by SIG 1S10OD019961-01).
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.
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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 -