scholarly journals Inhibition of RAS: proven and potential vulnerabilities

2020 ◽  
Vol 48 (5) ◽  
pp. 1831-1841
Author(s):  
Mariyam Zuberi ◽  
Imran Khan ◽  
John P. O'Bryan
Keyword(s):  
Human Cancer ◽  
Unmet Need ◽  
Cancer Therapeutics ◽  
Bound State ◽  
Small Gtpase ◽  
Apparent Lack ◽  
Downstream Effector ◽  
Ras Inhibition ◽  
Covalent Inhibitors ◽  
Effector Pathways

RAS is a membrane localized small GTPase frequently mutated in human cancer. As such, RAS has been a focal target for developing cancer therapeutics since its discovery nearly four decades ago. However, efforts to directly target RAS have been challenging due to the apparent lack of readily discernable deep pockets for binding small molecule inhibitors leading many to consider RAS as undruggable. An important milestone in direct RAS inhibition was achieved recently with the groundbreaking discovery of covalent inhibitors that target the mutant Cys residue in KRAS(G12C). Surprisingly, these G12C-reactive compounds only target mutant RAS in the GDP-bound state thereby locking it in the inactive conformation and blocking its ability to couple with downstream effector pathways. Building on this success, several groups have developed similar compounds that selectively target KRAS(G12C), with AMG510 and MRTX849 the first to advance to clinical trials. Both have shown early promising results. Though the success with these compounds has reignited the possibility of direct pharmacological inhibition of RAS, these covalent inhibitors are limited to treating KRAS(G12C) tumors which account for <15% of all RAS mutants in human tumors. Thus, there remains an unmet need to identify more broadly efficacious RAS inhibitors. Here, we will discuss the current state of RAS(G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function.

RAS GTPase signalling to alternative effector pathways

2020 ◽  
Vol 48 (5) ◽  
pp. 2241-2252
Author(s):  
Swati Singh ◽  
Matthew J. Smith
Keyword(s):  
Biological Significance ◽  
Small Gtpase ◽  
Effector Proteins ◽  
Acquired Drug Resistance ◽  
Binding Domains ◽  
Ras Gtpases ◽  
Downstream Effector ◽  
Cancer Initiation ◽  
Effector Pathways ◽  
Ras Signalling

RAS GTPases are fundamental regulators of development and drivers of an extraordinary number of human cancers. RAS oncoproteins constitutively signal through downstream effector proteins, triggering cancer initiation, progression and metastasis. In the absence of targeted therapeutics to mutant RAS itself, inhibitors of downstream pathways controlled by the effector kinases RAF and PI3K have become tools in the treatment of RAS-driven tumours. Unfortunately, the efficacy of this approach has been greatly minimized by the prevalence of acquired drug resistance. Decades of research have established that RAS signalling is highly complex, and in addition to RAF and PI3K these small GTPase proteins can interact with an array of alternative effectors that feature RAS binding domains. The consequence of RAS binding to these effectors remains relatively unexplored, but these pathways may provide targets for combinatorial therapeutics. We discuss here three candidate alternative effectors: RALGEFs, RASSF5 and AFDN, detailing their interaction with RAS GTPases and their biological significance. The metastatic nature of RAS-driven cancers suggests more attention should be granted to these alternate pathways, as they are highly implicated in the regulation of cell adhesion, polarity, cell size and cytoskeletal architecture.

scholarly journals Significance of Ras Signaling in Cancer and Strategies for its Control

2015 ◽  
Vol 11 (02) ◽  
pp. 147
Author(s):  
Arun Bahadur Gurung ◽  
Atanu Bhattacharjee ◽  
◽  
Keyword(s):  
Drug Targets ◽  
Cell Cycle Progression ◽  
Cancer Therapeutics ◽  
Ras Signaling ◽  
Post Translational Modification ◽  
Downstream Effector ◽  
Downstream Effectors ◽  
Ras Effectors ◽  
A Cell ◽  
Effector Pathways

Ras is a GTP-binding protein and is the most widely studied oncoprotein. To achieve its biological activity, it must undergo post-translation modification. Ras acts as a typical molecular switch. The GTP-bound Ras can activate several downstream effector pathways. Ras signaling regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. Several studies have found mutation in Ras or its effectors in various types of tumors. Therefore, Ras or its downstream effectors can be attractive drug targets against various types of tumors in cancer therapeutics. Some therapeutic agents against Ras effectors, such as Raf, MEK1/2, PI3K, AKT etc., have successfully managed to enter into phase I and II trials. This targeted drug design could be envisaged in mainly four ways, such as prevention of Ras-GTP formation, covalent locking of the GDP-bound Ras, inhibition of Ras-effector interactions, or impairment of post-translational modification of Ras. In this review we summarize the normal Ras signaling as well its aberrant signaling in tumors and various strategies to inhibit Ras signaling.

scholarly journals The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis

2019 ◽  
Vol 20 (15) ◽  
pp. 3612
Author(s):  
Laetitia Mouly ◽  
Julia Gilhodes ◽  
Anthony Lemarié ◽  
Elizabeth Cohen-Jonathan Moyal ◽  
Christine Toulas ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Predictive Marker ◽  
Bound State ◽  
Small Gtpase ◽  
Mrna Levels

The Rho GTPase family can be classified into classic and atypical members. Classic members cycle between an inactive Guanosine DiPhosphate -bound state and an active Guanosine TriPhosphate-bound state. Atypical Rho GTPases, such as RND1, are predominantly in an active GTP-bound conformation. The role of classic members in oncogenesis has been the subject of numerous studies, while that of atypical members has been less explored. Besides the roles of RND1 in healthy tissues, recent data suggest that RND1 is involved in oncogenesis and response to cancer therapeutics. Here, we present the current knowledge on RND1 expression, subcellular localization, and functions in healthy tissues. Then, we review data showing that RND1 expression is dysregulated in tumors, the molecular mechanisms involved in this deregulation, and the role of RND1 in oncogenesis. For several aggressive tumors, RND1 presents the features of a tumor suppressor gene. In these tumors, low expression of RND1 is associated with a bad prognosis for the patients. Finally, we highlight that RND1 expression is induced by anticancer agents and modulates their response. Of note, RND1 mRNA levels in tumors could be used as a predictive marker of both patient prognosis and response to anticancer agents.

scholarly journals The ERK MAPK pathway modulates Gq-dependent locomotion in >Caenorhabditis elegans

2017 ◽  
Author(s):  
Brantley Coleman ◽  
Irini Topalidou ◽  
Michael Ailion
Keyword(s):  
Caenorhabditis Elegans ◽  
Mapk Pathway ◽  
Acetylcholinesterase Inhibitor ◽  
Small Gtpase ◽  
C Elegans ◽  
Erk Mapk ◽  
Downstream Effector ◽  
Locomotion Behavior ◽  
Effector Pathways ◽  
Control Locomotion

AbstractThe heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical Gq effector phospholipase Cβ, the small GTPase Rho was recently identified as a conserved effector of Gq. To identify additional molecules important for Gq signaling in neurons, we performed a forward genetic screen in the nematode Caenorhabditis elegans for suppressors of the hyperactivity and exaggerated waveform of an activated Gq mutant. We isolated two mutations affecting the MAP kinase scaffold protein KSR-1 and found that KSR-1 modulates locomotion downstream of or in parallel to the Gq-Rho pathway. Through epistasis experiments, we found that the core ERK MAPK cascade is required for Gq-Rho regulation of locomotion, but that the canonical ERK activator LET-60/Ras may not be required. Through neuron-specific rescue experiments, we found that the ERK pathway functions in head acetylcholine neurons to control Gq-dependent locomotion. Additionally, expression of activated LIN-45/Raf in head acetylcholine neurons is sufficient to cause an exaggerated waveform phenotype and hypersensitivity to the acetylcholinesterase inhibitor aldicarb, similar to an activated Gq mutant. Taken together, our results suggest that the ERK MAPK pathway modulates the output of Gq-Rho signaling to control locomotion behavior in C. elegans.

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 433
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Revikumar Amjesh ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Targeted Therapeutics ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

scholarly journals The scaffold protein JIP3 functions as a downstream effector of the small GTPase ARF6 to regulate neurite morphogenesis of cortical neurons

FEBS Letters ◽  
2010 ◽  
Vol 584 (13) ◽  
pp. 2801-2806 ◽  
Author(s):  
Atsushi Suzuki ◽  
Chihiro Arikawa ◽  
Yuji Kuwahara ◽  
Kouichi Itoh ◽  
Masatomo Watanabe ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Scaffold Protein ◽  
Small Gtpase ◽  
Downstream Effector

scholarly journals Cardiac Glycoside Ouabain Exerts Anticancer Activity via Downregulation of STAT3

2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Du ◽  
Lijun Jiang ◽  
Fuqiang Chen ◽  
Huantao Hu ◽  
Meijuan Zhou
Keyword(s):  
Cardiac Glycosides ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Initiation Factor ◽  
Ros Generation ◽  
Dna Double Strand Breaks ◽  
Atpase Inhibitor ◽  
Anticancer Activities ◽  
Downstream Target ◽  
Human Cancer Cells

Cardiac glycosides are plant-derived steroid-like compounds which have been used for the treatment of cardiovascular diseases. Ouabain, a cardiotonic steroid and specific Na+/K+-ATPase inhibitor, has been rediscovered for its potential use in the treatment of cancer. However, the cellular targets and anticancer mechanism of ouabain in various cancers remain largely unexplored. In this study, we confirmed the cytotoxic effects of ouabain on several cancer cell lines. Further examination revealed the increase of apoptosis, intracellular ROS generation and DNA double-strand breaks induced by ouabain treatment. Besides, ouabain effectively suppressed STAT3 expression as well as phosphorylation in addition to block STAT3-mediated transcription and downstream target proteins. Interestingly, these inhibitory activities seemed to be independent of the Na+/K+-ATPase. Furthermore, we found that ouabain inhibited protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E binding protein 1 (4EBP1). Taken together, our study provided a novel molecular insight of anticancer activities of ouabain in human cancer cells, which could raise the hope of using cardiac glycosides for cancer therapeutics more rational.

scholarly journals Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5

2019 ◽  
Author(s):  
Xi Qiao ◽  
Ying Liu ◽  
Maria Llamazares Prada ◽  
Abhishekh Gupta ◽  
Alok Jaiswal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Breast Cancer Cells ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Cancer Tissue ◽  
Basal Type

AbstractMYC protein expression has to be tightly controlled to allow for maximal cell proliferation without inducing apoptosis. Here we discover UBR5 as a novel MYC ubiquitin ligase and demonstrate how it functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 effects on MYC protein stability are independent on N-terminal FBW7 degron of MYC. Endogenous UBR5 inhibition induces MYC protein expression and activates MYC target genes. Moreover, UBR5 governs MYC-dependent phenotypes in vivo in Drosophila. In cancer cells, UBR5-mediated MYC protein suppression diminishes cell killing activity of cancer therapeutics. Further, we demonstrate that UBR5 dominates MYC protein expression at the single-cell level in human basal-type breast cancer tissue. Myc and Ubr5 are co-amplified in MYC-driven human cancer types, and UBR5 controls MYC-mediated apoptotic threshold in co-amplified basal type breast cancer cells. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC protein expression in vivo. Clinically, expression of UBR5 may be important for protection of breast cancer cells from drug-induced, and MYC-dependent, apoptosis.

Rho activation in excitatory agonist-stimulated vascular smooth muscle

2001 ◽  
Vol 281 (2) ◽  
pp. C571-C578 ◽  
Author(s):  
Sotaro Sakurada ◽  
Hiroyuki Okamoto ◽  
Noriko Takuwa ◽  
Naotoshi Sugimoto ◽  
Yoh Takuwa
Keyword(s):  
Smooth Muscle ◽  
Kinase Inhibitor ◽  
Contractile Response ◽  
Rho Kinase ◽  
Small Gtpase ◽  
Dependent Manner ◽  
Aortic Smooth Muscle ◽  
Rhoa Activation ◽  
Downstream Effector ◽  
First Time

Small GTPase Rho and its downstream effector, Rho kinase, have been implicated in agonist-stimulated Ca2+ sensitization of 20-kDa myosin light chain (MLC20) phosphorylation and contraction in smooth muscle. In the present study we demonstrated for the first time that excitatory receptor agonists induce increases in amounts of an active GTP-bound form of RhoA, GTP-RhoA, in rabbit aortic smooth muscle. Using a pull-down assay with a recombinant RhoA-binding protein, Rhotekin, we found that a thromboxane A2 mimetic, U-46619, which induced a sustained contractile response, induced a sustained rise in the amount of GTP-RhoA in a dose-dependent manner with an EC50 value similar to that for the contractile response. U-46619-induced RhoA activation was thromboxane A2 receptor-mediated and reversible. Other agonists including norepinephrine, serotonin, histamine, and endothelin-1 (ET-1) also stimulated RhoA, albeit to lesser extents than U-46619. In contrast, ANG II and phorbol 12,13-dibutyrate failed to increase GTP-RhoA. The tyrosine kinase inhibitor genistein substantially inhibited RhoA activation by these agonists, except for ET-1. Thus excitatory agonists induce Rho activation in an agonist-specific manner, which is thought to contribute to stimulation of MLC20 phosphorylation Ca2+ sensitivity.

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