A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

Kale, Vijay P.; Hengst, Jeremy A.; Desai, Dhimant; Dick, Taryn E.; Choe, Katherine N.; Colledge, Ashley L.; Takahashi, Yoshinori; Sung, Shen Shu; Amin, Shantu; Yun, Jong K.

doi:10.1016/j.canlet.2014.08.032

Cited by 30 publications

(25 citation statements)

References 41 publications

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“…MRCKα expression is increased in a number of human cancers (Unbekandt and Olson, 2014) and dual inhibition of ROCK and MRCK activity has been shown to produce a greater inhibition of cancer cell migration and invasion than blocking ROCK alone (Wilkinson et al, 2005;Kale et al, 2014). Widely used ROCK inhibitors such as Y-27632 and fasudil bind to MRCKs (Heikkila et al, 2011), although these compounds also inhibit several other kinases and are not clinically viable (Bain et al, 2007).…”

Section: Myotonic Dystrophy Kinase-related Cdc42-binding Kinases (Mrcks)mentioning

confidence: 99%

Targeting Rho GTPase Signaling Networks in Cancer

Clayton

Ridley

2020

Front. Cell Dev. Biol.

139

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As key regulators of cytoskeletal dynamics, Rho GTPases coordinate a wide range of cellular processes, including cell polarity, cell migration, and cell cycle progression. The adoption of a pro-migratory phenotype enables cancer cells to invade the stroma surrounding the primary tumor and move toward and enter blood or lymphatic vessels. Targeting these early events could reduce the progression to metastatic disease, the leading cause of cancer-related deaths. Rho GTPases play a key role in the formation of dynamic actin-rich membrane protrusions and the turnover of cell-cell and cellextracellular matrix adhesions required for efficient cancer cell invasion. Here, we discuss the roles of Rho GTPases in cancer, their validation as therapeutic targets and the challenges of developing clinically viable Rho GTPase inhibitors. We review other therapeutic targets in the wider Rho GTPase signaling network and focus on the four best characterized effector families: p21-activated kinases (PAKs), Rho-associated protein kinases (ROCKs), atypical protein kinase Cs (aPKCs), and myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs).

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Section: Myotonic Dystrophy Kinase-related Cdc42-binding Kinases (Mrcks)mentioning

confidence: 99%

Targeting Rho GTPase Signaling Networks in Cancer

Clayton

Ridley

2020

Front. Cell Dev. Biol.

139

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“…Cancer cells have also been shown to switch modes of migration after ROCK inhibition, for instance, from rounded amoeboid type to elongated mesenchymal type in Y27632 treated gastric cancer cells (Matsuoka et al 2011 ). Drug combinations to simultaneously block several targets may produce greater anti-metastatic effects: combined inhibition of ROCK and Rac reduced mesenchymal motility of Y27632 treated gastric cancer cells (Matsuoka and Yashiro 2014 ; Matsuoka et al 2011 ); combined inhibition of ROCK and myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK) inhibited migration and invasion of lung, breast, melanoma, and pancreatic cancer cells (Kale et al 2014 , 2015 ). Finally, the recently developed new ROCK inhibitors with higher potency than Y27632 or fasudil may be more effective in blocking tumor cell invasion and metastasis (Sadok et al 2015 ).…”

Section: Rock Is a Key Player In Cancer Progressionmentioning

confidence: 99%

“…OXA-06 was used to show that anchorage-independent growth and matrigel invasion of non-small cell lung carcinoma cells were ROCK dependent (Vigil et al 2012 ). DJ4, a multi-kinase inhibitor of both ROCK and MRCK, inhibited migration and invasion of lung, breast, melanoma, and pancreatic cancer cells (Kale et al 2014 ). CCT129254 and AT13148, discovered as ATP-competitive AKT kinase inhibitors, also potently inhibited both ROCK1 and ROCK2 activity leading to a collapsed cytoskeletal phenotype, which was not observed in cells treated with less potent inhibitors Y27632 or H1152 (Sadok et al 2015 ).…”

Section: Promising Potential Of Rock Inhibition In Cancer Therapymentioning

confidence: 99%

Novel Insights into the Roles of Rho Kinase in Cancer

Wei

Surma

Shi

et al. 2016

Arch. Immunol. Ther. Exp.

174

134

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Rho-associated coiled-coil kinase (ROCK) is a major downstream effector of the small GTPase RhoA. The ROCK family, consisting of ROCK1 and ROCK2, plays a central role in the organization of the actin cytoskeleton, and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Since the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored in numerous diseases, including cancer. Accumulating evidence supports the concept that ROCK plays important roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance as well. This review focuses on the new advances of the most recent five years from the studies on the roles of ROCK in cancer development and progression; the discussion is mainly focused on the potential value of ROCK inhibitors in cancer therapy.

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“…ROCK functions as a serine/threonine kinase impacting CDH1-mediated cell adhesion, tumor microenvironment and actin structural biology. 10 , 80 , 81 CDH1, RHOA and ARHGAP defects are common and are mutually exclusive. Hp infection reportedly activates members of the RHO family of GTPases.…”

Section: Ebv-related Receptor Kinase Signalingmentioning

confidence: 99%

Genomic assays for Epstein–Barr virus-positive gastric adenocarcinoma

Gulley

2015

Exp Mol Med

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A small set of gastric adenocarcinomas (9%) harbor Epstein–Barr virus (EBV) DNA within malignant cells, and the virus is not an innocent bystander but rather is intimately linked to pathogenesis and tumor maintenance. Evidence comes from unique genomic features of host DNA, mRNA, microRNA and CpG methylation profiles as revealed by recent comprehensive genomic analysis by The Cancer Genome Atlas Network. Their data show that gastric cancer is not one disease but rather comprises four major classes: EBV-positive, microsatellite instability (MSI), genomically stable and chromosome instability. The EBV-positive class has even more marked CpG methylation than does the MSI class, and viral cancers have a unique pattern of methylation linked to the downregulation of CDKN2A (p16) but not MLH1. EBV-positive cancers often have mutated PIK3CA and ARID1A and an amplified 9p24.1 locus linked to overexpression of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). Multiple noncoding viral RNAs are highly expressed. Patients who fail standard therapy may qualify for enrollment in clinical trials targeting cancer-related human gene pathways or promoting destruction of infected cells through lytic induction of EBV genes. Genomic tests such as the GastroGenus Gastric Cancer Classifier are available to identify actionable variants in formalin-fixed cancer tissue of affected patients.

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A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

Cited by 30 publications

References 41 publications

Targeting Rho GTPase Signaling Networks in Cancer

Targeting Rho GTPase Signaling Networks in Cancer

Novel Insights into the Roles of Rho Kinase in Cancer

Genomic assays for Epstein–Barr virus-positive gastric adenocarcinoma

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