The ROCK-1/2 inhibitor RKI-1447 blocks N-MYC, promotes cell death, and emerges as a synergistic partner for BET inhibitors in neuroblastoma.

Autor: Pepich A; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden. Electronic address: adena.pepich@ki.se., Tümmler C; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Abu Ajamieh S; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Treis D; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Boje AS; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden; Division of Antibody-Based Immunotherapy, Department of Internal Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany., Vellema Q; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Tsea I; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Åkerlund E; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden., Seashore-Ludlow B; Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden., Shirazi Fard S; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Kogner P; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Johnsen JI; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden., Wickström M; Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden. Electronic address: malin.wickstrom@ki.se.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Nov 28; Vol. 605, pp. 217261. Date of Electronic Publication: 2024 Sep 20.
DOI: 10.1016/j.canlet.2024.217261
Abstrakt: High-risk neuroblastoma has a poor prognosis despite intensive treatment, highlighting the need for new therapeutic strategies. Genetic alterations in activators and inactivators of Rho GTPase have been identified in neuroblastoma suggested to activate Rho/Rho-kinase (ROCK) signaling. ROCK has also been implicated in therapy resistance. Therefore, we have explored the efficacy of the dual ROCK inhibitor RKI-1447 in neuroblastoma, emphasizing combination strategies. Treatment with RKI-1447 resulted in decreased growth, increased cell death, and inhibition of N-MYC in vitro and in vivo. A combination screen revealed enhanced effects between RKI-1447 and BET inhibitors. Synergistic effects from RKI-1447 and the BET inhibitor, ABBV-075, were confirmed in various neuroblastoma models, including zebrafish. Interestingly, ABBV-075 increased phosphorylation of both myosin light chain 2 and cofilin, downstream effectors of ROCK, increases that were blocked by adding RKI-1447. The combination treatment also augmented an inhibitory effect on C-MYC and, less pronounced, N-MYC protein expression. BET inhibitors have shown preclinical efficacy against neuroblastoma, but acquired resistance has limited their therapeutic benefit. We reveal that the combination of ROCK and BET inhibitors offers a promising treatment approach that can potentially mitigate resistance to BET inhibitors and reduce toxicity.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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