Inhibition of Rho-Associated Kinase Suppresses Medulloblastoma Growth

Abstract

Medulloblastoma is one of the most common malignant brain tumor types in children, with an overall survival of 70%. Mortality is associated with metastatic relapsed tumors. Rho-associated kinases (ROCKs), important for epithelial-mesenchymal transition (EMT) and proper nervous system development, have previously been identified as a promising drug target to inhibit cancer growth and metastatic spread. Here, we show that ROCKs are expressed in medulloblastoma, with higher ROCK2 mRNA expression in metastatic compared to non-metastatic tumors. By evaluating three ROCK inhibitors in a panel of medulloblastoma cell lines we demonstrated that medulloblastoma cells were sensitive for pharmacological ROCK inhibition. The specific ROCK inhibitor RKI-1447 inhibited the tumorigenicity in medulloblastoma cells as well as impeded cell migration and invasion. Differential gene expression analysis suggested that ROCK inhibition was associated with the downregulation of signaling pathways important in proliferation and metastasis e.g., TNFα via NFκβ, TGFβ, and EMT. Expression of key proteins in these pathways such as RHOA, RHOB, JUN, and vimentin was downregulated in ROCK inhibited cells. Finally, we showed that ROCK inhibition by RKI-1447 suppressed medulloblastoma growth and proliferation in vivo. Collectively, our results suggest that ROCK inhibition presents a potential new therapeutic option in medulloblastoma, especially for children with metastatic disease.

Mechanisms for Modulating Anoikis Resistance in Cancer and the Relevance of Metabolic Reprogramming

“…Another study showed that the overexpression of ROCK 2 in colon carcinoma cells which were inoculated into immunocompromised mice altered the epithelial morphology and promoted tumor cell invasiveness into the surrounding tissues ( 154 ). Also, targeting ROCK 1 and ROCK 2 blocked medulloblastoma proliferation through the impairment of EMT, TGF-β, and TNFα via NFkβ signaling ( 87 ), which suggests that blockade of ROCK signaling could be a target to impair anoikis resistance and metastasis. Although the role of Rho GTPase in cancer was reviewed ( 150 , 155 ), future studies are required to understand how targeting Rho GTPase can lead to the development of novel therapeutic agents for anoikis-resistant and metastasizing tumor cells.…”

Rho-Kinase as a Target for Cancer Therapy and Its Immunotherapeutic Potential

“…High expression of ROCK is associated with poor prognosis in medulloblastoma [ 45 ] neuroblastoma [ 46 ], and vascular tumors [ 47 ]. In medulloblastoma including metastatic medulloblastoma, mRNA levels of ROCK , especially ROCK2 , were highly expressed, which was associated with the overall survival of patients.…”

In situ immunogenic clearance induced by a combination of photodynamic therapy and rho-kinase inhibition sensitizes immune checkpoint blockade response to elicit systemic antitumor immunity against intraocular melanoma and its metastasis

“… 16 ROCK signaling is also involved in various tumorigenic pathways. 17 Ripasudil, a ROCK inhibitor, has been clinically approved for treating glaucoma and ocular hypertension in the form of an eye drop solution. Based on the immune-stimulatory effects of ROCK inhibitors, including enhancing the phagocytic activity of APCs and their ability to processing tumor antigens, and immediate cross-priming of naïve T cells, 18 ripasudil can be repurposed as an antitumor compound.…”