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

Rebecca Lee, Garima Khandelwal, Franziska Baenke, Alessio Cannistraci, Kenneth McCleod, Piyushkumar Mundra, Garry Ashton, Amit Mandal, Amaya Viros, Gabriela Gremel, Elena Galvani, Matthew Smith, Neil Carragher, Nathalie Dhoumen, Crispin Miller, Paul Lorigan, Richard Marais

Research output: Contribution to journalArticlepeer-review

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 therapy.

Methods
We performed whole-exome 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 up-regulation of the AKT/PI3kinase pathway in the presence of cerebrospinal fluid.

Conclusion
Heterogeneous tumour interactions within the brain microenvironment enables progression on immune and targeted therapy and should be targeted in salvage treatments.
Original languageEnglish
JournalESMO Open
DOIs
Publication statusPublished - 17 Aug 2020

Keywords

  • acral melanoma
  • immune therapy
  • targeted therapy
  • brain metastasis

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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