Show simple item record

dc.contributor.authorLee, Rebecca J
dc.contributor.authorKhandelwal, Garima
dc.contributor.authorBaenke, Franziska
dc.contributor.authorCannistraci, Alession
dc.contributor.authorMacleod, K.
dc.contributor.authorMundra, Piyushkumar A
dc.contributor.authorAshton, Garry
dc.contributor.authorMandal, Amit
dc.contributor.authorViros, Amaya
dc.contributor.authorGremel, Gabriela
dc.contributor.authorGalvani, Elena
dc.contributor.authorSmith, Matthew
dc.contributor.authorCarragher, N.
dc.contributor.authorDhomen, Nathalie
dc.contributor.authorMiller, Crispin J
dc.contributor.authorLorigan, Paul C
dc.contributor.authorMarais, Richard
dc.date.accessioned2020-09-16T11:57:57Z
dc.date.available2020-09-16T11:57:57Z
dc.date.issued2020en
dc.identifier.citationLee 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.en
dc.identifier.pmid32817058en
dc.identifier.doi10.1136/esmoopen-2020-000707en
dc.identifier.urihttp://hdl.handle.net/10541/623260
dc.description.abstractBackground: 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.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1136/esmoopen-2020-000707en
dc.titleBrain microenvironment-driven resistance to immune and targeted therapies in acral melanomaen
dc.typeArticleen
dc.contributor.departmentMolecular Oncology Group, CRUK Manchester Institute, The University of Manchester, Nether Alderley, Macclesfield, UK.en
dc.identifier.journalESMO Openen
dc.description.noteen]
refterms.dateFOA2020-09-21T09:11:15Z


Files in this item

Thumbnail
Name:
Brain RJLee.pdf
Size:
2.101Mb
Format:
PDF
Description:
From UNPAYWALL

This item appears in the following Collection(s)

Show simple item record