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

Pepich A, Tümmler C, Abu Ajamieh S, Treis D, Boje AS, Vellema Q, Tsea I, Åkerlund E, Seashore-Ludlow B, Shirazi Fard S, Kogner P, Johnsen JI, Wickström M

Cancer Lett. 605 (-) 217261 [2024-11-28; online 2024-09-20]

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.

PubMed 39307412

DOI 10.1016/j.canlet.2024.217261

Crossref 10.1016/j.canlet.2024.217261

pii: S0304-3835(24)00656-6