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.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…BRAF inhibitor resistance involves a range of transcription factors ( Table 2 ) [ 14 , 16 , 22 , 28 , 45 , 46 , 48 , 52 , 58 , 66 , 81 , 89 , 97 , 117 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. A transcriptomic analysis of BRAF inhibitor-resistant melanoma cells showed that some transcription factors were upregulated whereas others were downregulated [ 141 ].…”

“…Epigenetic mechanisms may be targeted by inhibiting key transcription factors, such as WNT5 or STAT3 [ 134 , 135 , 222 , 240 ], or by the use of microRNA mimetics [ 59 ] or HDAC inhibitors [ 111 , 163 , 241 , 242 , 243 , 244 , 245 ]. HDAC inhibitors have also been investigated in combination with a CDK inhibitor with promising in vitro and in vivo activity [ 233 , 244 , 246 ].…”

RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy

“…Unfortunately, patients receiving BRAF inhibitors (BRAFi) relapses after several months of monotherapy because of the acquired resistance (Nazarian et al, 2010). WNT5A was shown to play a crucial role in the process leading to the Vemurafenib resistance (Anastas et al, 2014;Mohapatra et al, 2018;O'Connell et al, 2013;Prasad et al, 2015;Webster et al, 2015). Therefore, we were interested to check whether RNF43 inhibits via its effects on WNT5A signaling cellular plasticity in response to Vemurafenib (PLX4032), a clinically used BRAF V600E inhibitor.…”

Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition

“…4 IL-6 signals directly to tumor cells through at least three major signaling pathways, including janus-activated kinase 1/2 (JAK1/2)/signal transactivator of transcription 3 (STAT3), rat sarcoma (RAS)/mitogen-activated protein kinase (MAPK), and phosphoinositide-3 kinase (PI3K)/AKR Thymoma (AKT), contributing to tumor promotion by expansion and survival of malignant cells, neo-angiogenesis, and inflammation. [5][6][7][8][9][10][11] IL-6 can also be secreted from infiltrating myeloid cells such as tumor-associated macrophages, dendritic cells (DC) and myeloid-derived suppressor cells (MDSC), 8 12 and tumor-associated stroma such as cancer-associated fibroblasts, endothelial, or senescent cells, contributing to a dynamic tumor-fibroblast cross-talk in the tumor microenvironment. 13 High levels of IL-6 exist in many pathologic conditions including cancer and rheumatologic diseases.…”