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.
Highlights
In a more recent report, we demonstrated that IL-6 and WNT5A signalling constitute a positive feedback loop that potentiates the migration and invasion of melanoma cells (Linnskog et al, 2016)
We checked for increased WNT5A expression, which is another established characteristic of BRAF inhibitor (BRAFi) resistance in melanoma (Anastas et al, 2014; O’Connell et al, 2013)
We explored possible changes in the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRb), since these receptors have previously been related to BRAFi resistance in melanomas (Vella et al, 2017; Wang et al, 2015)
Summary
The majority of cancers are caused and promoted by either inherited or acquired genetic changes. The ‘V600E’ mutation in the BRAF gene is the most commonly observed mutation. Patients with melanoma bearing such a cancer-driving mutation can be effectively treated with a BRAF inhibitor (BRAFi), Abbreviations Box, t-butyloxycarbonyl-modified WNT5A-derived hexapeptide; BRAFi, BRAF inhibitor; BRAFi-R, BRAF inhibitor-resistant; IL-6 Ab, anti-human interleukin-6 antibody; IL-6, Interleukin-6. Molecular Oncology 13 (2019) 480–494 a 2018 The Authors.
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