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Effects of the JAK2-selective inhibitors NVP-BSK805 and NVP-BVB808 in BCR-ABL or JAK2 mutation-positive cell lines

Ringel, Frauke and Kaeda, Jaspal and Schwarz, Michaela and Oberender, Christian and Grille, Peggy and Doerken, Bernd and Marque, Fanny and Manley, Paul W. and Radimerski, Thomas and le Coutre, Philippe (2014) Effects of the JAK2-selective inhibitors NVP-BSK805 and NVP-BVB808 in BCR-ABL or JAK2 mutation-positive cell lines. Haematologica, 132 (1). pp. 75-86. ISSN 1421-9662

Abstract

Janus kinases are critical components of cytokine signaling pathways that regulate hematopoiesis, growth, immunity, inflammation, and development. Oncogenic mutations of the non-receptor tyrosine kinase JAK2 are found in many Philadelphia chromosome negative myeloproliferative neoplasms. Preclinical results strongly support the concept that JAK2 inhibitors could be effectively usedshow efficacy in treating patients with chronic myeloproliferative neoplasms (CMPN). JAK2 has also been postulated to play an important role in BCR-ABL signal transduction. Therefore, inhibitors of the tyrosine kinase activity of JAK2 are under investigation as new therapeutic strategies for treatment of CML. In this study the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergistic effects between NVP-BSK805 / NVP-BVB808 and the already established tyrosine kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed an intense response in the JAK2 mutated cell lines CHRF-288-11, SET-2 and UKE-1. Interestingly, the JAK2 V617F-positive HEL cells showed only a weak response. All BCR-ABL positive cell lines showed some reduction of proliferation, but with GI50 values higher than 1 µM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination with nilotinib did not show this effect.

Item Type: Article
Date Deposited: 08 May 2016 23:45
Last Modified: 08 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/8309

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