期刊
BRITISH JOURNAL OF CANCER
卷 123, 期 7, 页码 1101-1113出版社
SPRINGERNATURE
DOI: 10.1038/s41416-020-0996-2
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资金
- National Health and Medical Research Council (NHMRC) [114461]
- Rory Williams Fund
- Kids Cancer Centre
- Sydney Children's Hospital
- Australian Sarcoma Study Group Xavier Krikori Grant
- Australian Government Australian Postgraduate Award
- Kids Cancer Alliance
- Children's Cancer Institute
Background Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. Methods Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. Results Xenografts were validated by confirmation ofRANBP2-ALKrearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. Conclusions CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive,ALK-rearranged malignancies.
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