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

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.

• Authors: Stephen Mok, Jennifer Tsoi, Richard C Koya, Siwen Hu-Lieskovan, Brian L West, Gideon Bollag, Thomas G Graeber, Antoni Ribas
• Journal: BMC cancer (BMC Cancer) Vol. 15 Pg. 356 (May 05 2015) ISSN: 1471-2407 [Electronic] England
• PMID: 25939769 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Indoles
• Pyrroles
• Sulfonamides
• Vemurafenib
• pexidartinib
• Receptor, Macrophage Colony-Stimulating Factor
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Aminopyridines (administration & dosage)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Drug Synergism
• Indoles (administration & dosage)
• Lymphocyte Activation
• Macrophages (drug effects, immunology)
• Melanoma, Experimental (drug therapy, immunology)
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Transplantation
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors)
• Pyrroles (administration & dosage)
• Receptor, Macrophage Colony-Stimulating Factor (antagonists & inhibitors)
• Sulfonamides (administration & dosage)
• T-Lymphocytes (drug effects, immunology)
• Vemurafenib