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Updated: Jun 12, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
The ROCK-1/2 inhibitor RKI-1447 blocks N-MYC, promotes cell death, and emerges as a synergistic partner for BET
Adena Pepich1, Conny Tümmler1, Sara Abu Ajamieh1
1Division of Pediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Sweden.
Abstract:
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.
Insights
This study shows that combining Rho-kinase (ROCK) inhibitors with BET inhibitors effectively treats neuroblastoma. This combination therapy may overcome resistance and reduce side effects in patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- High-risk neuroblastoma presents a significant therapeutic challenge due to poor prognosis and treatment resistance.
- Aberrant Rho GTPase signaling, particularly Rho-kinase (ROCK) pathway activation, is implicated in neuroblastoma development and therapy resistance.
Purpose of the Study:
- To investigate the efficacy of the dual ROCK inhibitor RKI-1447 as a monotherapy and in combination for neuroblastoma treatment.
- To explore synergistic interactions between RKI-1447 and BET inhibitors, aiming to overcome resistance and enhance therapeutic outcomes.
Main Methods:
- In vitro and in vivo studies using neuroblastoma cell lines and animal models.
- Combination drug screening to identify synergistic therapeutic partners for RKI-1447.
- Assessment of molecular targets including N-MYC, C-MYC, and downstream ROCK effectors.
Main Results:
- RKI-1447 monotherapy demonstrated anti-proliferative and pro-apoptotic effects, inhibiting N-MYC expression.
- Combination of RKI-1447 with BET inhibitor ABBV-075 exhibited synergistic effects across multiple neuroblastoma models.
- The combination therapy modulated ROCK signaling pathways and enhanced inhibition of MYC family proteins.
Conclusions:
- Dual ROCK inhibition with RKI-1447 is a viable strategy for neuroblastoma.
- Combining ROCK and BET inhibitors presents a promising therapeutic approach for neuroblastoma, potentially mitigating resistance and reducing toxicity associated with BET inhibitors alone.
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