In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts.
Document Type
Article
Publication Date
6-20-2023
Original Citation
Hughes K,
Evans K,
Earley E,
Smith C,
Erickson S,
Stearns T,
Philip VM,
Neuhauser S,
Chuang J,
Jocoy E,
Bult C,
Teicher B,
Smith M,
Lock R.
In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts. Pediatr Blood Cancer. 2023;70(9):e30503.
Keywords
JMG
JAX Source
Pediatr Blood Cancer. 2023;70(9):e30503.
ISSN
1545-5017
PMID
37339930
DOI
https://doi.org/10.1002/pbc.30503
Grant
National Cancer Institute, Grant/Award Numbers: CA199000, CA199222, CA263963; National Health and Medical Research Council of Australia, Grant/Award Number: APP1157871
Abstract
BACKGROUND: While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs).
METHODS: SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45
RESULTS: FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45
CONCLUSIONS: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.