Preclinical to clinical utility of ROCK inhibitors in cancer

Barcelo, Jaume; Samain, Rémi; Sanz‐Moreno, Victoria

doi:10.1016/j.trecan.2022.12.001

Cited by 22 publications

(12 citation statements)

References 89 publications

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“…We suggest a decrease in the highly aggressive amoeboid cancer cell populations as a marker of response in the ongoing clinical trials using CD73 targeting drugs (NCT04940286 and NCT04148937) in PDAC. ROCKi ( 70 ) could also be considered in this context.…”

Section: Discussionmentioning

confidence: 99%

CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

Samain,

Maiques,

Monger

et al. 2023

Sci. Adv.

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Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK–Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA–ROCK–Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73–ROCK–Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

Samain,

Maiques,

Monger

et al. 2023

Sci. Adv.

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“…However, it should be noted that the safety and feasibility of ROCK2 inhibition in humans has already been established with belumosudil, an orally available selective ROCK2 inhibitor, in patients with chronic graft-versus-host disease 22 . In addition, clinical trials with ROCK2 inhibitors targeting diffuse cutaneous systemic sclerosis are ongoing 23 . Further trials involving ROCK2 inhibitors with the goal of reducing the risk of an abnormal kidney function and death would engender additional confidence.…”

Section: Discussionmentioning

confidence: 99%

Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis

Matoba,

Nagai,

Sekiguchi

et al. 2024

Commun Biol

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Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.

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“…The breakthrough findings of the importance of RhoA/MRTFs/SRF transcription in cardiovascular, neurodegenerative, and intestinal diseases and fibrosis to cancer tumorigenesis and metastasis have been much appreciated [ 36 , 37 , 38 , 39 ]. Research in cancer therapeutics has highlighted the importance of molecularly targeted therapies, and such inhibitors of Rho kinase are currently under clinical trials in cancer [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function

Patyal,

Zhang,

Verma

et al. 2024

Cells

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RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics.

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Preclinical to clinical utility of ROCK inhibitors in cancer

Cited by 22 publications

References 89 publications

CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis

Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function

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