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    Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma

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    Authors
    Lee, Rebecca J
    Khandelwal, Garima
    Baenke, Franziska
    Cannistraci, Alession
    Macleod, K.
    Mundra, Piyushkumar A
    Ashton, Garry
    Mandal, Amit Kumar
    Viros, Amaya
    Gremel, Gabriela
    Galvani, Elena
    Smith, Matthew
    Carragher, N.
    Dhomen, Nathalie
    Miller, Crispin J
    Lorigan, Paul C
    Marais, Richard
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    Affiliation
    Molecular Oncology Group, CRUK Manchester Institute, The University of Manchester, Nether Alderley, Macclesfield, UK.
    Issue Date
    2020
    
    Metadata
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    Abstract
    Background: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. Methods: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. Results: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. Conclusion: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments. Keywords: acral melanoma; brain metastasis; immune therapy; targeted therapy.
    Citation
    Lee RJ, Khandelwal G, Baenke F, Cannistraci A, Macleod K, Mundra P, et al. Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma. ESMO Open. 2020;5(4):e000707.
    Journal
    ESMO Open
    URI
    http://hdl.handle.net/10541/623260
    DOI
    10.1136/esmoopen-2020-000707
    PubMed ID
    32817058
    Additional Links
    https://dx.doi.org/10.1136/esmoopen-2020-000707
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1136/esmoopen-2020-000707
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