Soluble AXL as a marker of disease progression and survival in melanoma.

Karine Flem-Karlsen,Kari Dolven Jacobsen,Erin Mcfadden,Vivi Ann Flørenes,Inger Nina Farstad,Patrik Wernhoff,Marta Nyakas,Gunhild Mari Mælandsmo,Nikolas K Haass

doi:10.1371/journal.pone.0227187

Karine Flem-Karlsen, Kari Dolven Jacobsen + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0227187

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Abstract

Receptor tyrosine kinase AXL is a one-pass transmembrane protein upregulated in cancers and associated with lower survival and therapy resistance. AXL can be cleaved by the A Disintegrin and Metalloproteinases (ADAM)10 and ADAM17, yielding a soluble version of the protein. Elevated soluble AXL (sAXL) has been reported to be associated with disease progression in hepatocellular carcinoma, renal cancer, neurofibromatosis type 1 and inflammatory diseases. In the present work, we analyzed sAXL levels in blood from melanoma patients and showed that sAXL increases with disease progression. Additionally, increased sAXL levels were found correlated with shorter two-year survival in stage IV patients treated with ipilimumab. Furthermore, we showed that sAXL levels were related to the percentage of cells expressing AXL in resected melanoma lymph node metastases. This finding was verified in vitro, where sAXL levels in the cell media corresponded to AXL expression in the cells. AXL inhibition using the small-molecular inhibitor BGB324 reduced sAXL levels, while the cellular expression was elevated through increased protein stability. Our findings signify that quantification of sAXL blood levels is a simple and easily assessable method to determine cellular AXL levels and should be further evaluated for its use as a biomarker of disease progression and treatment response.

Highlights

Melanoma is among the cancers with the highest increase in incidence worldwide [1]
The results showed increased cellular expression of AXL, while soluble AXL (sAXL) levels in the media were reduced by 30–40% following BGB324 treatment (Fig 2B and 2C) (p value Melmet 1 = 0.006 and A375 = 0.004), without affecting proliferation (S2C Fig) The increased cellular expression of AXL was not caused by increased transcription, as no increase in AXL mRNA levels following treatment with BGB324 was observed (S2D Fig)
It has been reported that BGB324 induces mRNA expression of the A Disintegrin and Metalloproteinases (ADAM) inhibitor TIMP1 [24]

Summary

Introduction

Melanoma is among the cancers with the highest increase in incidence worldwide [1]. Treatment of melanoma is challenging due to high intratumoral heterogeneity and therapy resistance [2,3,4]. Immunotherapies, such as monoclonal antibodies targeting CTLA-4 and PD-1, have become first line treatment. While the response is quite favorable in a fraction of the patients, these treatments are costly and come with significant side effects and there is currently no method for identifying non-responding patients [5]. Small-molecular inhibitors targeting the ERK/MAPK pathway, which comprise BRAF and MEK inhibition.

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