Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia.

Autor: Bӧhm JW; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Sia KCS; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Jones C; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Evans K; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Mariana A; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Pang I; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia., Failes T; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Zhong L; Bioanalytical Mass Spectrometry Facility, UNSW Sydney, Sydney, NSW, Australia., Mayoh C; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Landman R; Incyte Corporation, Wilmington, DE, USA., Collins R; Incyte Corporation, Wilmington, DE, USA., Erickson SW; RTI International, Research Triangle Park, NC, USA., Arndt G; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Raftery MJ; Bioanalytical Mass Spectrometry Facility, UNSW Sydney, Sydney, NSW, Australia., Wilkins MR; School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia., Norris MD; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Haber M; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia., Marshall GM; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.; Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia., Lock RB; Children's Cancer Institute, School of Women's and Children's Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. rlock@ccia.unsw.edu.au.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2021 Nov; Vol. 35 (11), pp. 3101-3112. Date of Electronic Publication: 2021 Apr 24.
DOI: 10.1038/s41375-021-01248-8
Abstrakt: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL subtype with high rates of relapse and poor patient outcome. Activating mutations affecting components of the JAK-STAT signaling pathway occur in the majority of Ph-like ALL cases. The use of JAK inhibitors represents a potential treatment option for Ph-like ALL, although we and others have shown that CRLF2-rearranged Ph-like ALL responds poorly to single-agent JAK inhibitors in the preclinical setting. Therefore, the aim of this study was to identify effective combination treatments against CRLF2-rearranged Ph-like ALL, and to elucidate the underlying mechanisms of synergy. We carried out a series of high-throughput combination drug screenings and found that ruxolitinib exerted synergy with standard-of-care drugs used in the treatment of ALL. In addition, we investigated the molecular effects of ruxolitinib on Ph-like ALL by combining mass spectrometry phosphoproteomics with gene expression analysis. Based on these findings, we conducted preclinical in vivo drug testing and demonstrated that ruxolitinib enhanced the in vivo efficacy of an induction-type regimen consisting of vincristine, dexamethasone, and L-asparaginase in 2/3 CRLF2-rearranged Ph-like ALL xenografts. Overall, our findings support evaluating the addition of ruxolitinib to conventional induction regimens for the treatment of CRLF2-rearranged Ph-like ALL.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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