Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600Emelanoma

Ngiow, Shin F., Meeth, Katrina M., Stannard, Kimberley, Barkauskas, Deborah S., Bollag, Gideon, Bosenberg, Marcus and Smyth, Mark J. (2016) Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600Emelanoma. OncoImmunology, 5 3: e1089381-1-e1089381-11. doi:10.1080/2162402X.2015.1089381


Author Ngiow, Shin F.
Meeth, Katrina M.
Stannard, Kimberley
Barkauskas, Deborah S.
Bollag, Gideon
Bosenberg, Marcus
Smyth, Mark J.
Title Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600Emelanoma
Formatted title
Co-inhibition of colony stimulating factor-1 receptor and BRAF oncogene in mouse models of BRAFV600E melanoma
Journal name OncoImmunology   Check publisher's open access policy
ISSN 2162-402X
Publication date 2016-03-03
Year available 2015
Sub-type Article (original research)
DOI 10.1080/2162402X.2015.1089381
Open Access Status Not Open Access
Volume 5
Issue 3
Start page e1089381-1
End page e1089381-11
Total pages 11
Place of publication New York, NY United States
Publisher Taylor & Francis
Collection year 2016
Language eng
Formatted abstract
The presence of colony stimulating factor-1 (CSF1)/CSF1 receptor (CSF1R)-driven tumor-infiltrating macrophages and myeloid-derived suppressor cells (MDSCs) is shown to promote targeted therapy resistance. In this study, we demonstrate the superior effect of a combination of CSF1R inhibitor, PLX3397 and BRAF inhibitor, PLX4720, in suppressing primary and metastatic mouse BRAFV600E melanoma. Using flow cytometry to assess SM1WT1 melanoma-infiltrating leukocytes immediately post therapy, we found that PLX3397 reduced the recruitment of CD11b+ Gr1lo and CD11b+ Gr1int M2-like macrophages, but this was accompanied by an accumulation of CD11b+ Gr1hi cells. PDL1 expression on remaining myeloid cells potentially dampened the antitumor efficacy of PLX3397 and PLX4720 in combination, since PD1/PDL1 axis blockade improved outcome. We also reveal a role for PLX3397 in reducing tumor-infiltrating lymphocytes, and interestingly, this feature was rescued by the co-administration of PLX4720. Our findings, from three different mouse models of BRAF-mutated melanoma, support clinical approaches that co-target BRAF oncogene and CSF1R.
Keyword BRAFV600E
BRAF inhibitor
CSF1R
Melanoma
M2 macrophage
PLX4720
PLX3397
Tumor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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