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

Abstract

Cancer immunotherapy is fast rising as a prominent new pillar of cancer treatment, harnessing the immune system to fight against numerous types of cancer. Rho-kinase (ROCK) pathway is involved in diverse cellular activities, and is therefore the target of interest in various diseases at the cellular level including cancer. Indeed, ROCK is well-known for its involvement in the tumor cell and tumor microenvironment, especially in its ability to enhance tumor cell progression, migration, metastasis, and extracellular matrix remodeling. Importantly, ROCK is also considered to be a novel and effective modulator of immune cells, although further studies are needed. In this review article, we describe the various activities of ROCK and its potential to be utilized in cancer treatment, particularly in cancer immunotherapy, by shining a light on its activities in the immune system.

RHOA takes the RHOad less traveled to cancer

“…These findings are in line with the enhanced binding of RHOA Y42C to ROCK in gastric cancer [65]. An emerging number of studies involves ROCK in regulating tumor-promoting inflammation and immune responses, identifying it as a promising target for immunotherapy in cancer [66,67].…”

“…Pharmacological inhibition of PI3K (PI3Ki) was shown to enhance sensitivity to anti-PD-1 immune checkpoint inhibitor therapy. and immune cells in different cancers [4,66,67]. In recent years, several ROCK inhibitors (e.g., AT13148) with a higher efficacy than first-generation inhibitors (e.g., Y-27632) have been developed (summarized in [66,67]), with one (AT13148) in a clinical trial for solid tumors, predominantly colorectal cancer [68].…”

Amoeboid migration in health and disease: Immune responses versus cancer dissemination

“…ROCK inhibitors show clear anti-tumour effects in in vivo mouse models ( Liu et al, 2009 ; Georgouli et al, 2019 ; Orgaz et al, 2020 ; Rodriguez-Hernandez et al, 2020 ; Kim et al, 2021 ). Targeting Rho GTPases within immune cells has been explored for the treatment of chronic inflammatory disorders ( Biro et al, 2014 ).…”

“…Targeting Rho GTPases within immune cells has been explored for the treatment of chronic inflammatory disorders ( Biro et al, 2014 ). However, more work is needed to understand if ROCK inhibitors affect anti-tumour immunity ( Kim et al, 2021 ). Migrastatics, including ROCK inhibitors, could be used to prevent metastatic disease ( Gandalovičová et al, 2017 ; Maiques et al, 2021 ), but this needs to be carefully considered within the context of complex tumour environments and administration routes ( Rath and Olson, 2012 ).…”

“…ROCK inhibitors are approved to treat glaucoma ( Honjo and Tanihara, 2018 ), cerebral vasospasm ( Zhao et al, 2006 ) and graft vs. host disease ( Ali and Ilyas, 2022 ), and are currently being tested for numerous diseases, including cancer ( Crosas-Molist et al, 2021 ). ROCK inhibitors could be utilised for combination therapies, for example ROCK inhibitor/BRAF inhibitor and ROCK inhibitor/αPD-1 ( Orgaz et al, 2020 ), alongside other chemotherapeutic agents ( Kim et al, 2021 ), or via dual target inhibition ( McLeod et al, 2020 ). Alternatively, local application for skin cancers, drug delivery systems (e.g., nanoparticles), antibody drug conjugates or oncolytic viruses could be explored, although these avenues are in early stage development ( Senapati et al, 2018 ; Krishnan and Mitragotri, 2020 ; Yao et al, 2020 ).…”