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

Orsolya Giricz, Yongkai Mo, Kimberly B. Dahlman, Xiomaris M. Cotto-Rios, Chiara Vardabasso, Hoa Nguyen, Bernice Matusow, Matthias Bartenstein, Veronika Polishchuk, Douglas B. Johnson, Tushar D. Bhagat, Rafe Shellooe, Elizabeth Burton, James Tsai, Chao Zhang, Gaston Habets, John M. Greally, Yiting Yu, Paraic A. Kenny, Gregg B. FieldsKith Pradhan, E. Richard Stanley, Emily Bernstein, Gideon Bollag, Evripidis Gavathiotis, Brian L. West, Jeffrey A. Sosman, Amit K. Verma

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number14
DOIs
StatePublished - Jul 26 2018

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Melanoma
Macrophage Colony-Stimulating Factor Receptors
Methylation
Cytosine
RNA Interference
Epigenomics
Phosphotransferases
Up-Regulation
Ligands
Mutation
Growth
Neoplasms
Therapeutics

Keywords

  • Melanoma
  • Oncology

Cite this

The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma. / Giricz, Orsolya; Mo, Yongkai; Dahlman, Kimberly B.; Cotto-Rios, Xiomaris M.; Vardabasso, Chiara; Nguyen, Hoa; Matusow, Bernice; Bartenstein, Matthias; Polishchuk, Veronika; Johnson, Douglas B.; Bhagat, Tushar D.; Shellooe, Rafe; Burton, Elizabeth; Tsai, James; Zhang, Chao; Habets, Gaston; Greally, John M.; Yu, Yiting; Kenny, Paraic A.; Fields, Gregg B.; Pradhan, Kith; Stanley, E. Richard; Bernstein, Emily; Bollag, Gideon; Gavathiotis, Evripidis; West, Brian L.; Sosman, Jeffrey A.; Verma, Amit K.

In: JCI insight, Vol. 3, No. 14, 26.07.2018.

Research output: Contribution to journalArticle

Giricz, O, Mo, Y, Dahlman, KB, Cotto-Rios, XM, Vardabasso, C, Nguyen, H, Matusow, B, Bartenstein, M, Polishchuk, V, Johnson, DB, Bhagat, TD, Shellooe, R, Burton, E, Tsai, J, Zhang, C, Habets, G, Greally, JM, Yu, Y, Kenny, PA, Fields, GB, Pradhan, K, Stanley, ER, Bernstein, E, Bollag, G, Gavathiotis, E, West, BL, Sosman, JA & Verma, AK 2018, 'The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma', JCI insight, vol. 3, no. 14. https://doi.org/10.1172/jci.insight.120422
Giricz, Orsolya ; Mo, Yongkai ; Dahlman, Kimberly B. ; Cotto-Rios, Xiomaris M. ; Vardabasso, Chiara ; Nguyen, Hoa ; Matusow, Bernice ; Bartenstein, Matthias ; Polishchuk, Veronika ; Johnson, Douglas B. ; Bhagat, Tushar D. ; Shellooe, Rafe ; Burton, Elizabeth ; Tsai, James ; Zhang, Chao ; Habets, Gaston ; Greally, John M. ; Yu, Yiting ; Kenny, Paraic A. ; Fields, Gregg B. ; Pradhan, Kith ; Stanley, E. Richard ; Bernstein, Emily ; Bollag, Gideon ; Gavathiotis, Evripidis ; West, Brian L. ; Sosman, Jeffrey A. ; Verma, Amit K. / The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma. In: JCI insight. 2018 ; Vol. 3, No. 14.
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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.",
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AU - Giricz, Orsolya

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.

PY - 2018/7/26

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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.

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