Combination therapy targeting the elevated interleukin‐6 level reduces invasive migration of BRAF inhibitor‐resistant melanoma cells

Abstract

The identification of novel antimetastatic therapeutic targets is necessary for improved treatment of patients with acquired BRAF inhibitor‐resistant (BRAFi‐R) melanoma, in whom metastasis is a major concern. Our present study focused on the identification of such targets to explore novel antimetastatic therapeutic options for BRAFi‐R melanoma patients. We confirmed the development of BRAFi resistance in our BRAFi‐treated melanoma cell lines by demonstrating reduced sensitivity to BRAF inhibitors, increased ERK1/2 activity and increased WNT5A expression. Here, we demonstrated for the first time that high secretion of interleukin‐6 (IL‐6) was associated with increased invasive migration of BRAFi‐R melanoma cells. This finding could be readily explained by the increased expression of WNT5A in BRAFi‐R melanoma cells and the presence of an IL‐6/WNT5A positive feedback loop in parental melanoma cells. Surprisingly, however, we found that the IL‐6/WNT5A positive feedback loop present in parental melanoma cells was lost during the development of acquired BRAFi resistance, meaning that IL‐6 and WNT5A signalling were independent events in BRAFi‐R melanoma cells. Despite the absence of an IL‐6/WNT5A loop, we found that both an IL‐6 blocking antibody and the WNT5A antagonist Box5 alone impaired the elevated invasive migration of BRAFi‐R melanoma cells, but combined use of the two was more effective. This impaired invasive migration of BRAFi‐R melanoma cells correlated well with the reduction in Cdc42‐GTPase activity and alterations of the actin cytoskeleton in these cells. In summary, our novel identification of IL‐6 as a key independent promoter of the invasive migration of BRAFi‐R melanoma cells stresses that a combination of a blocking IL‐6 antibody and administration of the WNT5A antagonist Box5 might be an attractive antimetastatic approach for future treatment of BRAFi‐R melanoma patients.

Keywords

• BRAF inhibitor‐resistant
• interleukin‐6
• invasion
• melanoma
• migration
• WNT5A