Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant...

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.