CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma.
ATP Binding Cassette Transporter, Subfamily B, Member 1
/ antagonists & inhibitors
Aged, 80 and over
Anaplastic Lymphoma Kinase
/ antagonists & inhibitors
Animals
Brentuximab Vedotin
/ therapeutic use
Drug Resistance, Neoplasm
Gene Rearrangement
Humans
Inflammation
Ki-1 Antigen
/ antagonists & inhibitors
Male
Mice
Molecular Chaperones
/ genetics
Myofibroblasts
/ pathology
Nuclear Pore Complex Proteins
/ genetics
Sarcoma
/ drug therapy
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
01
02
2020
accepted:
01
07
2020
revised:
17
06
2020
pubmed:
21
7
2020
medline:
24
3
2021
entrez:
21
7
2020
Statut:
ppublish
Résumé
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. Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. Xenografts were validated by confirmation of RANBP2-ALK rearrangement, 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. 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.
Sections du résumé
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 of RANBP2-ALK rearrangement, 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.
Identifiants
pubmed: 32684628
doi: 10.1038/s41416-020-0996-2
pii: 10.1038/s41416-020-0996-2
pmc: PMC7524717
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B, Member 1
0
Ki-1 Antigen
0
Molecular Chaperones
0
Nuclear Pore Complex Proteins
0
ran-binding protein 2
0
Brentuximab Vedotin
7XL5ISS668
ALK protein, human
EC 2.7.10.1
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1101-1113Références
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