scholarly journals Decoding RAS isoform and codon-specific signalling

2014 ◽  
Vol 42 (4) ◽  
pp. 742-746 ◽  
Author(s):  
Anna U. Newlaczyl ◽  
Fiona E. Hood ◽  
Judy M. Coulson ◽  
Ian A. Prior
Keyword(s):  
Present Article ◽  
Ras Proteins ◽  
Oncogenic Mutations ◽  
Underlying Mechanisms ◽  
Ras Isoforms

RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms.

scholarly journals RAS Nanoclusters Selectively Sort Distinct Lipid Headgroups and Acyl Chains

2021 ◽  
Vol 8 ◽  
Author(s):  
Yong Zhou ◽  
Alemayehu A. Gorfe ◽  
John F. Hancock
Keyword(s):  
Splice Variants ◽  
Small Gtpases ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Macromolecular Assembly ◽  
Oncogenic Mutations ◽  
Constitutively Active Mutants ◽  
Primary Location ◽  
Acyl Chains ◽  
Ras Isoforms

RAS proteins are lipid-anchored small GTPases that switch between the GTP-bound active and GDP-bound inactive states. RAS isoforms, including HRAS, NRAS and splice variants KRAS4A and KRAS4B, are some of the most frequently mutated proteins in cancer. In particular, constitutively active mutants of KRAS comprise ∼80% of all RAS oncogenic mutations and are found in 98% of pancreatic, 45% of colorectal and 31% of lung tumors. Plasma membrane (PM) is the primary location of RAS signaling in biology and pathology. Thus, a better understanding of how RAS proteins localize to and distribute on the PM is critical to better comprehend RAS biology and to develop new strategies to treat RAS pathology. In this review, we discuss recent findings on how RAS proteins sort lipids as they undergo macromolecular assembly on the PM. We also discuss how RAS/lipid nanoclusters serve as signaling platforms for the efficient recruitment of effectors and signal transduction, and how perturbing the PM biophysical properties affect the spatial distribution of RAS isoforms and their functions.

scholarly journals Advances in the Etiology, Detection, and Clinical Management of Seborrheic Keratoses

Dermatology ◽  
2021 ◽  
pp. 1-13
Author(s):  
Mary D. Sun ◽  
Allan C. Halpern
Keyword(s):  
Therapeutic Potential ◽  
Malignant Tumors ◽  
Treatment Options ◽  
Current Treatment ◽  
Diagnostic Methods ◽  
Treatment Standards ◽  
Oncogenic Mutations ◽  
Malignant State ◽  
Underlying Mechanisms ◽  
Seborrheic Keratoses

Seborrheic keratoses (SKs) are ubiquitous, generally benign skin tumors that exhibit high clinical variability. While age is a known risk factor, the precise roles of UV exposure and immune abnormalities are currently unclear. The underlying mechanisms of this benign disorder are paradoxically driven by oncogenic mutations and may have profound implications for our understanding of the malignant state. Advances in molecular pathogenesis suggest that inhibition of Akt and APP, as well as existing treatments for skin cancer, may have therapeutic potential in SK. Dermoscopic criteria have also become increasingly important to the accurate detection of SK, and other noninvasive diagnostic methods, such as reflectance confocal microscopy and optical coherence tomography, are rapidly developing. Given their ability to mimic malignant tumors, SK cases are often used to train artificial intelligence-based algorithms in the computerized detection of skin disease. These technologies are becoming increasingly accurate and have the potential to significantly augment clinical practice. Current treatment options for SK cause discomfort and can lead to adverse post-treatment effects, especially in skin of color. In light of the discontinuation of ESKATA in late 2019, promising alternatives, such as nitric-zinc and trichloroacetic acid topicals, should be further developed. There is also a need for larger, head-to-head trials of emerging laser therapies to ensure that future treatment standards address diverse patient needs.

Ras proteins as therapeutic targets

2018 ◽  
Vol 46 (5) ◽  
pp. 1303-1311 ◽  
Author(s):  
Atanu Chakraborty ◽  
Emily Linnane ◽  
Sarah Ross
Keyword(s):  
Therapeutic Strategies ◽  
Targeted Therapeutics ◽  
Ras Proteins ◽  
Ras Genes ◽  
Small Molecule Drug ◽  
Oncogenic Mutations ◽  
Recent Developments ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic ◽  
Made In

Oncogenic mutations in RAS genes underlie the pathogenesis of many human tumours, and there has been intense effort for over 30 years to develop effective and tolerated targeted therapeutics for patients with Ras-driven cancers. This review summarises the progress made in Ras drug discovery, highlighting some of the recent developments in directly targeting Ras through advances in small molecule drug design and novel therapeutic strategies.

scholarly journals Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders

2020 ◽  
Vol 117 (22) ◽  
pp. 12121-12130
Author(s):  
Yao-Cheng Li ◽  
Nikki K. Lytle ◽  
Seth T. Gammon ◽  
Luke Wang ◽  
Tikvah K. Hayes ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Developmental Disorders ◽  
Degradation Pathway ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Ras Proteins ◽  
Ras Protein ◽  
Protein Levels ◽  
Ras Family ◽  
Ras Isoforms

HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS–RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome–lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.

scholarly journals Small molecule inhibitors of RAS proteins with oncogenic mutations

2020 ◽  
Vol 39 (4) ◽  
pp. 1107-1126 ◽  
Author(s):  
Zoltán Orgován ◽  
György M. Keserű
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Molecular Switches ◽  
Membrane Association ◽  
Ras Proteins ◽  
Direct Inhibition ◽  
Cellular Processes ◽  
Oncogenic Mutations ◽  
Covalent Inhibitors ◽  
Ras Signalling

AbstractRAS proteins control a number of essential cellular processes as molecular switches in the human body. Presumably due to their important signalling role, RAS proteins are among the most frequently mutated oncogenes in human cancers. Hence, numerous efforts were done to develop appropriate therapies for RAS-mutant cancers in the last three decades. This review aimed to collect all of the reported small molecules that affect RAS signalling. These molecules can be divided in four main branches. First, we address approaches blocking RAS membrane association. Second, we focus on the stabilization efforts of non-productive RAS complexes. Third, we examine the approach to block RAS downstream signalling through disturbance of RAS-effector complex formation. Finally, we discuss direct inhibition; particularly the most recently reported covalent inhibitors, which are already advanced to human clinical trials.

scholarly journals Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Raymond R. Mattingly
Keyword(s):  
Mek Inhibitor ◽  
Ras Proteins ◽  
Wild Type ◽  
Farnesyl Transferase ◽  
Oncogenic Ras ◽  
Effective Inhibition ◽  
Ras Isoforms ◽  
And Function ◽  
Made In

The ability to selectively and directly target activated Ras would provide immense utility for treatment of the numerous cancers that are driven by oncogenic Ras mutations. Patients with disorders driven by overactivated wild-type Ras proteins, such as type 1 neurofibromatosis, might also benefit from progress made in that context. Activated Ras is an extremely challenging direct drug target due to the inherent difficulties in disrupting the protein:protein interactions that underlie its activation and function. Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. Likely reasons for this disappointing outcome include the significant and underappreciated differences in the isoforms of Ras. It is still plausible that inhibition of farnesyl transferase will prove effective for disease that is driven by activated H-Ras. The principal current focus of drugs entering clinic trial is inhibition of pathways downstream of activated Ras, for example, trametinib, a first-in-class MEK inhibitor. The complexity of signaling that is driven by activated Ras indicates that effective inhibition of oncogenic transduction through this approach will be difficult, with resistance being likely to emerge through switch to parallel pathways. Durable disease responses will probably require combinatorial block of several downstream targets.

scholarly journals Activated K-Ras and H-Ras display different interactions with saturable nonraft sites at the surface of live cells

2002 ◽  
Vol 157 (5) ◽  
pp. 865-872 ◽  
Author(s):  
Hagit Niv ◽  
Orit Gutman ◽  
Yoel Kloog ◽  
Yoav I. Henis
Keyword(s):  
Fluorescent Protein ◽  
Lateral Diffusion ◽  
Live Cells ◽  
Ras Proteins ◽  
Membrane Interactions ◽  
Mobility Studies ◽  
Membrane Compartments ◽  
Green Fluorescent ◽  
Ras Isoforms ◽  
Membrane Anchoring

Ras–membrane interactions play important roles in signaling and oncogenesis. H-Ras and K-Ras have nonidentical membrane anchoring moieties that can direct them to different membrane compartments. Ras–lipid raft interactions were reported, but recent studies suggest that activated K-Ras and H-Ras are not raft resident. However, specific interactions of activated Ras proteins with nonraft sites, which may underlie functional differences and phenotypic variation between different Ras isoforms, are unexplored. Here we used lateral mobility studies by FRAP to investigate the membrane interactions of green fluorescent protein–tagged H- and K-Ras in live cells. All Ras isoforms displayed stable membrane association, moving by lateral diffusion and not by exchange with a cytoplasmic pool. The lateral diffusion rates of constitutively active K- and H-Ras increased with their expression levels in a saturable manner, suggesting dynamic association with saturable sites or domains. These sites are distinct from lipid rafts, as the activated Ras mutants are not raft resident. Moreover, they appear to be different for H- and K-Ras. However, wild-type H-Ras, the only isoform preferentially localized in rafts, displayed cholesterol-sensitive interactions with rafts that were independent of its expression level. Our findings provide a mechanism for selective signaling by different Ras isoforms.

scholarly journals Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3311
Author(s):  
Hadia Moindjie ◽  
Sylvie Rodrigues-Ferreira ◽  
Clara Nahmias
Keyword(s):  
Mitochondrial Dynamics ◽  
Redox Homeostasis ◽  
Gene Mutations ◽  
Neoplastic Cell ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Oncogenic Mutations ◽  
Promising Target ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of oncogenic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Mitochondria are central organelles at the crossroad of various energetic metabolisms. In addition to their pivotal roles in bioenergetic metabolism, they control redox homeostasis, biosynthesis of macromolecules and apoptotic signals, all of which are linked to carcinogenesis. In the present review, we discuss how mitochondria contribute to the initiation of carcinogenesis through gene mutations and production of oncometabolites, and how they promote tumor progression through the control of metabolic reprogramming and mitochondrial dynamics. Finally, we present mitochondrial metabolism as a promising target for the development of novel therapeutic strategies.

scholarly journals Bispecific antibodies targeting mutantRASneoantigens

2021 ◽  
Vol 6 (57) ◽  
pp. eabd5515 ◽  
Author(s):  
Jacqueline Douglass ◽  
Emily Han-Chung Hsiue ◽  
Brian J. Mog ◽  
Michael S. Hwang ◽  
Sarah R. DiNapoli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Leukocyte ◽  
Bispecific Antibodies ◽  
Ras Proteins ◽  
Single Chain ◽  
Hla Alleles ◽  
Oncogenic Mutations ◽  
Low Levels

Mutations in theRASoncogenes occur in multiple cancers, and ways to target these mutations has been the subject of intense research for decades. Most of these efforts are focused on conventional small-molecule drugs rather than antibody-based therapies because the RAS proteins are intracellular. Peptides derived from recurrentRASmutations, G12V and Q61H/L/R, are presented on cancer cells in the context of two common human leukocyte antigen (HLA) alleles, HLA-A3 and HLA-A1, respectively. Using phage display, we isolated single-chain variable fragments (scFvs) specific for each of these mutant peptide-HLA complexes. The scFvs did not recognize the peptides derived from the wild-type form of RAS proteins or other related peptides. We then sought to develop an immunotherapeutic agent that was capable of killing cells presenting very low levels of theseRAS-derived peptide-HLA complexes. Among many variations of bispecific antibodies tested, one particular format, the single-chain diabody (scDb), exhibited superior reactivity to cells expressing low levels of neoantigens. We converted the scFvs to this scDb format and demonstrated that they were capable of inducing T cell activation and killing of target cancer cells expressing endogenous levels of the mutant RAS proteins and cognate HLA alleles. CRISPR-mediated alterations of theHLAandRASgenes provided strong genetic evidence for the specificity of the scDbs. Thus, this approach could be applied to other common oncogenic mutations that are difficult to target by conventional means, allowing for more specific anticancer therapeutics.

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