Abstract
The vascular endothelial growth factor receptor‐1 (VEGFR‐1) is a tyrosine kinase receptor frequently expressed in melanoma. Its activation by VEGF‐A or placental growth factor (PlGF) promotes tumour cell survival, migration and invasiveness. Moreover, VEGFR‐1 stimulation contributes to pathological angiogenesis and induces recruitment of tumour‐associated macrophages. Since melanoma acquired resistance to BRAF inhibitors (BRAFi) has been associated with activation of pro‐angiogenic pathways, we have investigated VEGFR‐1 involvement in vemurafenib resistance. Results indicate that human melanoma cells rendered resistant to vemurafenib secrete greater amounts of VEGF‐A and express higher VEGFR‐1 levels compared with their BRAFi‐sensitive counterparts. Transient VEGFR‐1 silencing in susceptible melanoma cells delays resistance development, whereas in resistant cells it increases sensitivity to the BRAFi. Consistently, enforced VEGFR‐1 expression, by stable gene transfection in receptor‐negative melanoma cells, markedly reduces sensitivity to vemurafenib. Moreover, melanoma cells expressing VEGFR‐1 are more invasive than VEGFR‐1 deficient cells and receptor blockade by a specific monoclonal antibody (D16F7 mAb) reduces extracellular matrix invasion triggered by VEGF‐A and PlGF. These data suggest that VEGFR‐1 up‐regulation might contribute to melanoma progression and spreading after acquisition of a drug‐resistant phenotype. Thus, VEGFR‐1 inhibition with D16F7 mAb might be a suitable adjunct therapy for VEGFR‐1 positive tumours with acquired resistance to vemurafenib.
Highlights
The vascular endothelial growth factor receptor‐1 (VEGFR‐1) is a membrane tyrosine kinase receptor for VEGF‐A, VEGF‐B and pla‐ cental growth factor (PlGF) that are all members of the VEGF fam‐ ily of angiogenic factors.[1]
We demonstrate for the first time that the up‐regulation of another receptor tyrosine kinase, VEGFR‐1, participates to the development of a resistant phenotype in melanoma
Human melanoma cells rendered resistant to the BRAF inhibitors (BRAFi) express higher VEGFR‐1 levels compared with their BRAFi‐sensitive counterparts
Summary
The vascular endothelial growth factor receptor‐1 (VEGFR‐1) is a membrane tyrosine kinase receptor for VEGF‐A, VEGF‐B and pla‐ cental growth factor (PlGF) that are all members of the VEGF fam‐ ily of angiogenic factors.[1]. Besides genetic alterations that result in reactivation of the MAPK and, less frequently, activation of the PI3K‐Akt pathways, other mechanisms are involved in acquired resistance to BRAF inhibitors (BRAFi) including activation of pro‐an‐ giogenic pathways.[19,20] In this regard, the onset of treatment resis‐ tance to the BRAFi dabrafenib is associated with restored VEGF‐A production by melanoma cells.[21,22,23] by paradoxically activating the MAPK pathway in BRAF wild‐type macrophages, BRAFi may induce the production of VEGF‐A, which directly stim‐ ulates macrophage survival, tumour immune evasion and melanoma growth.[20,24,25] treatment of susceptible BRAF mutated melanoma with BRAFi results in reduced tumour vascularity and increased T cell infiltration in melanoma that was attributed to loss or reduced VEGF‐A expression and secretion.[26,27,28]. The results indicate that human melanoma cells rendered re‐ sistant to the BRAFi vemurafenib express higher levels of VEGFR‐1 compared to their BRAFi‐sensitive counterparts and that inhibition of VEGFR‐1 with D16F7 mAb might be a suitable adjunct therapy for VEGFR‐1 positive tumours with acquired resistance to vemurafenib
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