1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Toward Minimal Residual Disease-Directed Therapy in Melanoma

          Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

            Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial.

              There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial.
                Bookmark

                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: Project administrationRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: SoftwareRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 January 2020
                2020
                : 15
                : 1
                : e0227187
                Affiliations
                [1 ] Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
                [2 ] Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
                [3 ] Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
                [4 ] Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
                [5 ] Institute of Medical Biology, Faculty of Health Sciences, UiT–Arctic University of Norway, Tromsø, Norway
                University of Queensland Diamantina Institute, AUSTRALIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-8405-3406
                http://orcid.org/0000-0001-6331-3440
                Article
                PONE-D-19-20864
                10.1371/journal.pone.0227187
                6952099
                31917795
                086aaaab-7323-4d80-b4b5-5a175a6e3297
                © 2020 Flem-Karlsen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 July 2019
                : 14 December 2019
                Page count
                Figures: 5, Tables: 2, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100006095, Helse Sør-Øst RHF;
                Award ID: 39873
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100006095, Helse Sør-Øst RHF;
                Award ID: 39873
                Award Recipient :
                Funded by: Bodil and Magnes Foundation
                Award ID: .
                Award Recipient :
                This work was supported by the following grants: KFK, EM: Southern and Eastern Norway Regional Health Authority (Project number 39873) and MN: Bodil and Magnes Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Melanomas
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Biology and Life Sciences
                Anatomy
                Lymphatic System
                Lymph Nodes
                Medicine and Health Sciences
                Anatomy
                Lymphatic System
                Lymph Nodes
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Enzyme-Linked Immunoassays
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Research and Analysis Methods
                Biological Cultures
                Cell Cultures
                Cultured Tumor Cells
                Melanoma Cells
                Research and Analysis Methods
                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
                Research and Analysis Methods
                Immunologic Techniques
                Immunohistochemistry Techniques
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article