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BMC Cancer. 2015 May 5;15:356. doi: 10.1186/s12885-015-1377-8.

Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition.

Mok S1,2, Tsoi J3, Koya RC4,5, Hu-Lieskovan S6, West BL7, Bollag G8, Graeber TG9,10,11, Ribas A12,13,14,15.

Author information

1
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. smok1@mdanderson.org.
2
MD Anderson Cancer Center, Houston, Texas, USA. smok1@mdanderson.org.
3
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. jtsoi@mednet.ucla.edu.
4
Department of Surgery, Division of Surgical Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. Richard.Koya@RoswellPark.org.
5
Roswell Park Cancer Institute, Buffalo, New York, USA. Richard.Koya@RoswellPark.org.
6
Department of Medicine, Division of Hematology/Oncology, UCLA, University of California Los Angeles (UCLA), 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1782, USA. SHu-Lieskovan@mednet.ucla.edu.
7
Plexxikon Inc, Berkeley, California, USA. bwest@plexxikon.com.
8
Plexxikon Inc, Berkeley, California, USA. gbollag@plexxikon.com.
9
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. TGraeber@mednet.ucla.edu.
10
Crump Institute for Molecular Imaging, UCLA, University of California Los Angeles (UCLA), Los Angeles, CA, USA. TGraeber@mednet.ucla.edu.
11
Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles (UCLA), Los Angeles, CA, USA. TGraeber@mednet.ucla.edu.
12
Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. aribas@mednet.ucla.edu.
13
Department of Surgery, Division of Surgical Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA. aribas@mednet.ucla.edu.
14
Department of Medicine, Division of Hematology/Oncology, UCLA, University of California Los Angeles (UCLA), 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1782, USA. aribas@mednet.ucla.edu.
15
Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles (UCLA), Los Angeles, CA, USA. aribas@mednet.ucla.edu.

Abstract

BACKGROUND:

Malignant melanoma is an aggressive tumor type that often develops drug resistance to targeted therapeutics. The production of colony stimulating factor 1 (CSF-1) in tumors recruits myeloid cells such as M2-polarized macrophages and myeloid derived suppressor cells (MDSC), leading to an immune suppressive tumor milieu.

METHODS:

We used the syngeneic mouse model of BRAF (V600E) -driven melanoma SM1, which secretes CSF-1, to evaluate the ability of the CSF-1 receptor (CSF-1R) inhibitor PLX3397 to improve the antitumor efficacy of the oncogenic BRAF inhibitor vemurafenib.

RESULTS:

Combined BRAF and CSF-1R inhibition resulted in superior antitumor responses compared with either therapy alone. In mice receiving PLX3397 treatment, a dramatic reduction of tumor-infiltrating myeloid cells (TIM) was observed. In this model, we could not detect a direct effect of TIMs or pro-survival cytokines produced by TIMs that could confer resistance to PLX4032 (vemurafenib). However, the macrophage inhibitory effects of PLX3397 treatment in combination with the paradoxical activation of wild type BRAF-expressing immune cells mediated by PLX4032 resulted in more tumor-infiltrating lymphocytes (TIL). Depletion of CD8+ T-cells abrogated the antitumor response to the combination therapy. Furthermore, TILs isolated from SM1 tumors treated with PLX3397 and PLX4032 displayed higher immune potentiating activity.

CONCLUSIONS:

The combination of BRAF-targeted therapy with CSF-1R blockade resulted in increased CD8 T-cell responses in the SM1 melanoma model, supporting the ongoing evaluation of this therapeutic combination in patients with BRAF (V600) mutant metastatic melanoma.

PMID:
25939769
PMCID:
PMC4432503
DOI:
10.1186/s12885-015-1377-8
[Indexed for MEDLINE]
Free PMC Article

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