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  1. Article ; Online: Ras in cancer and developmental diseases.

    Fernández-Medarde, Alberto / Santos, Eugenio

    Genes & cancer

    2011  Volume 2, Issue 3, Page(s) 344–358

    Abstract: ... updating current knowledge on the contribution of Ras mutations and altered Ras signaling to development ... with a variety of cancers. Interestingly, the oncogenic Ras mutations and the mutations in other components ... tumors, separate studies have identified germline mutations in Ras and various other components of Ras ...

    Abstract Somatic, gain-of-function mutations in ras genes were the first specific genetic alterations identified in human cancer about 3 decades ago. Studies during the last quarter century have characterized the Ras proteins as essential components of signaling networks controlling cellular proliferation, differentiation, or survival. The oncogenic mutations of the H-ras, N-ras, or K-ras genes frequently found in human tumors are known to throw off balance the normal outcome of those signaling pathways, thus leading to tumor development. Oncogenic mutations in a number of other upstream or downstream components of Ras signaling pathways (including membrane RTKs or cytosolic kinases) have been detected more recently in association with a variety of cancers. Interestingly, the oncogenic Ras mutations and the mutations in other components of Ras/MAPK signaling pathways appear to be mutually exclusive events in most tumors, indicating that deregulation of Ras-dependent signaling is the essential requirement for tumorigenesis. In contrast to sporadic tumors, separate studies have identified germline mutations in Ras and various other components of Ras signaling pathways that occur in specific association with a number of different familial, developmental syndromes frequently sharing common phenotypic cardiofaciocutaneous features. Finally, even without being a causative force, defective Ras signaling has been cited as a contributing factor to many other human illnesses, including diabetes and immunological and inflammatory disorders. We aim this review at summarizing and updating current knowledge on the contribution of Ras mutations and altered Ras signaling to development of various tumoral and nontumoral pathologies.
    Language English
    Publishing date 2011-07-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2538519-7
    ISSN 1947-6027 ; 1947-6019
    ISSN (online) 1947-6027
    ISSN 1947-6019
    DOI 10.1177/1947601911411084
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.

    Rauen, Katherine A / Tidyman, William E

    Disease models & mechanisms

    2024  Volume 17, Issue 6

    Abstract: ... of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here ... and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss ... RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants ...

    Abstract RASopathies are rare developmental genetic syndromes caused by germline pathogenic variants in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Although the incidence of each RASopathy syndrome is rare, collectively, they represent one of the largest groups of multiple congenital anomaly syndromes and have severe developmental consequences. Here, we review our understanding of how RAS/MAPK dysregulation in RASopathies impacts skeletal muscle development and the importance of RAS/MAPK pathway regulation for embryonic myogenesis. We also discuss the complex interactions of this pathway with other intracellular signaling pathways in the regulation of skeletal muscle development and growth, and the opportunities that RASopathy animal models provide for exploring the use of pathway inhibitors, typically used for cancer treatment, to correct the unique skeletal myopathy caused by the dysregulation of this pathway.
    MeSH term(s) Humans ; Animals ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; ras Proteins/metabolism ; Muscle Development/genetics ; Signal Transduction ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/metabolism ; Disease Models, Animal
    Chemical Substances ras Proteins (EC 3.6.5.2) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2024-06-07
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.050609
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Eliminating oncogenic RAS: back to the future at the drawing board.

    Steffen, Candy Laura / Kaya, Pelin / Schaffner-Reckinger, Elisabeth / Abankwa, Daniel

    Biochemical Society transactions

    2023  Volume 51, Issue 1, Page(s) 447–456

    Abstract: ... creative ideas continue to be important to exterminate RAS in cancer and other RAS pathway-driven diseases ... the development of allele-specific covalent and non-covalent RAS inhibitors, the potential of macromolecular ... binders to facilitate the discovery and validation of targetable sites on RAS and finally an outlook ...

    Abstract RAS drug development has made enormous strides in the past ten years, with the first direct KRAS inhibitor being approved in 2021. However, despite the clinical success of covalent KRAS-G12C inhibitors, we are immediately confronted with resistances as commonly found with targeted drugs. Previously believed to be undruggable due to its lack of obvious druggable pockets, a couple of new approaches to hit this much feared oncogene have now been carved out. We here concisely review these approaches to directly target four druggable sites of RAS from various angles. Our analysis focuses on the lessons learnt during the development of allele-specific covalent and non-covalent RAS inhibitors, the potential of macromolecular binders to facilitate the discovery and validation of targetable sites on RAS and finally an outlook on a future that may engage more small molecule binders to become drugs. We foresee that the latter could happen mainly in two ways: First, non-covalent small molecule inhibitors may be derived from the development of covalent binders. Second, reversible small molecule binders could be utilized for novel targeting modalities, such as degraders of RAS. Provided that degraders eliminate RAS by recruiting differentially expressed E3-ligases, this approach could enable unprecedented tissue- or developmental stage-specific destruction of RAS with potential advantages for on-target toxicity. We conclude that novel creative ideas continue to be important to exterminate RAS in cancer and other RAS pathway-driven diseases, such as RASopathies.
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras) ; Antineoplastic Agents/therapeutic use ; Oncogenes ; Neoplasms/genetics ; Genes, ras ; Mutation
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Antineoplastic Agents
    Language English
    Publishing date 2023-01-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20221343
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The impact of RAS mutation on the treatment strategy of colorectal cancer.

    Pirvu, Edvina Elena / Severin, Emilia / Niţă, Irina / Toma, Ştefania Andreea

    Medicine and pharmacy reports

    2023  Volume 96, Issue 1, Page(s) 5–15

    Abstract: ... present in 30% of patients with localized disease and in almost half of the patients that develop ... metastatic disease. While the development of chemotherapy doublets and targeted therapy have improved ... survival in recent years, KRAS mutation still has a controversial role regarding its prognostic and ...

    Abstract Kirsten rat sarcoma (KRAS) is the most frequently mutated oncogene in colorectal cancer, being present in 30% of patients with localized disease and in almost half of the patients that develop metastatic disease. While the development of chemotherapy doublets and targeted therapy have improved survival in recent years, KRAS mutation still has a controversial role regarding its prognostic and predictive value both in the adjuvant and in the metastatic setting. The impact of KRAS mutation on treatment strategy remains to be better defined. The development of new KRAS inhibitors promising new treatment options is on the horizon.
    Language English
    Publishing date 2023-01-25
    Publishing country Romania
    Document type Journal Article ; Review
    ZDB-ID 2974425-8
    ISSN 2668-0572 ; 2602-0807
    ISSN (online) 2668-0572
    ISSN 2602-0807
    DOI 10.15386/mpr-2408
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Crystallographic Studies of KRAS in Complex with Small Molecules and RAS-Binding Proteins.

    Chan, Albert H / Simanshu, Dhirendra K

    Methods in molecular biology (Clifton, N.J.)

    2024  Volume 2797, Page(s) 47–65

    Abstract: RAS proteins play a vital role in regulating downstream signaling and essential cellular processes ... These mutations disrupt the RAS protein's inherent ability to transition between its active and inactive states ... structural analysis of KRAS with inhibitors and RAS-binding proteins play a pivotal role in unraveling ...

    Abstract RAS proteins play a vital role in regulating downstream signaling and essential cellular processes, positioning them as key players in normal cellular physiology and disease development. Among the various isoforms of RAS, KRAS stands out as one of the most frequently mutated genes in human cancer. The prevalence of RAS mutations in cancer often involves single amino acid substitutions at codons 12, 13, or 61. These mutations disrupt the RAS protein's inherent ability to transition between its active and inactive states, resulting in a constant activation signal and driving uncontrolled cell growth. Crystallization and structural analysis of KRAS with inhibitors and RAS-binding proteins play a pivotal role in unraveling the structural and mechanistic details of KRAS function, aiding in drug discovery efforts, and advancing our understanding of KRAS-driven diseases. Here, we present our experimental methodology for crystallizing KRAS in the presence of covalent or non-covalent small molecules and proteins acting as effectors or regulators of RAS. We detail the techniques for successful crystallization and the subsequent optimization of crystallization conditions. The resulting crystals and their structures will provide valuable insights into the key interactions between KRAS and its partner proteins or potential inhibitors, offering a foundation for developing targeted therapies that are more potent and selective against KRAS-driven cancers.
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Carrier Proteins/metabolism ; ras Proteins/genetics ; ras Proteins/metabolism ; Signal Transduction ; Neoplasms/genetics ; Mutation
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Carrier Proteins ; ras Proteins (EC 3.6.5.2) ; KRAS protein, human
    Language English
    Publishing date 2024-03-23
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-3822-4_5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The RAS oncogene in brain tumors and the involvement of let-7 microRNA.

    Messina, Samantha

    Molecular biology reports

    2024  Volume 51, Issue 1, Page(s) 531

    Abstract: ... such as RAS, HMGA, c-Myc, cyclin-D and thus suppresses cancer development, differentiation and progression ... in gliomagenesis, and KRAS is undoubtedly a driving gene in gliomagenesis in mice. In cancer, microRNAs (miRNA) are ... an oncogenic RAS mutation that promotes disease progression (colon, lung, pancreas). In contrast, brain tumors ...

    Abstract RAS oncogenes are master regulator genes in many cancers. In general, RAS-driven cancers have an oncogenic RAS mutation that promotes disease progression (colon, lung, pancreas). In contrast, brain tumors are not necessarily RAS-driven cancers because RAS mutations are rarely observed. In particular, glioblastomas (the most lethal brain tumor) do not appear to have dominant genetic mutations that are suitable for targeted therapy. Standard treatment for most brain tumors continues to focus on maximal surgical resection, radiotherapy and chemotherapy. Yet the convergence of genomic aberrations such as EGFR, PDGFR and NF1 (some of which are clinically effective) with activation of the RAS/MAPK cascade is still considered a key point in gliomagenesis, and KRAS is undoubtedly a driving gene in gliomagenesis in mice. In cancer, microRNAs (miRNA) are small, non-coding RNAs that regulate carcinogenesis. However, the functional consequences of aberrant miRNA expression in cancer are still poorly understood. let-7 encodes an intergenic miRNA that is classified as a tumour suppressor, at least in lung cancer. Let-7 suppresses a plethora of oncogenes such as RAS, HMGA, c-Myc, cyclin-D and thus suppresses cancer development, differentiation and progression. let-7 family members are direct regulators of certain RAS family genes by binding to the sequences in their 3'untranslated region (3'UTR). let-7 miRNA is involved in the malignant behaviour in vitro-proliferation, migration and invasion-of gliomas and stem-like glioma cells as well as in vivo models of glioblastoma multiforme (GBM) via KRAS inhibition. It also increases resistance to certain chemotherapeutic agents and radiotherapy in GBM. Although let-7 therapy is not yet established, this review updates the current state of knowledge on the contribution of miRNA let-7 in interaction with KRAS to the oncogenesis of brain tumours.
    MeSH term(s) Animals ; Mice ; Genes, ras ; Proto-Oncogene Proteins p21(ras)/genetics ; ras Proteins/genetics ; MicroRNAs/metabolism ; Brain Neoplasms/metabolism ; Glioblastoma/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Cell Line, Tumor
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2) ; MicroRNAs
    Language English
    Publishing date 2024-04-18
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 186544-4
    ISSN 1573-4978 ; 0301-4851
    ISSN (online) 1573-4978
    ISSN 0301-4851
    DOI 10.1007/s11033-024-09439-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: RAS: Circuitry and therapeutic targeting.

    Singh, Gagandeep / Thakur, Neelam / Kumar, Umesh

    Cellular signalling

    2022  Volume 101, Page(s) 110505

    Abstract: ... states that favor cancer cells' growth, survival, plasticity and metastasis. Therefore, understanding RAS ... process. Despite advanced understanding of the genomic underpinning of cancer development and progression ... Cancer has affected the lives of millions worldwide and is truly regarded as a devastating disease ...

    Abstract Cancer has affected the lives of millions worldwide and is truly regarded as a devastating disease process. Despite advanced understanding of the genomic underpinning of cancer development and progression, therapeutic challenges are still persistent. Among all the human cancers, around 33% are attributed to mutations in RAS oncogene, a crucial component of the signaling pathways. With time, our understanding of RAS circuitry has improved and now the fact that it activates several downstream effectors, depending on the type and grades of cancer has been established. The circuitry is controlled via post-transcriptional mechanisms and frequent distortions in these mechanisms lead to important metabolic as well as immunological states that favor cancer cells' growth, survival, plasticity and metastasis. Therefore, understanding RAS circuitry can help researchers/clinicians to develop novel and potent therapeutics that, in turn, can save the lives of patients suffering from RAS-mutant cancers. There are many challenges presented by resistance and the potential strategies with a particular focus on novel combinations for overcoming these, that could move beyond transitory responses in the direction of treatment. Here in this review, we will look at how understanding the circuitry of RAS can be put to use in making strategies for developing therapeutics against RAS- driven malignancies.
    MeSH term(s) Humans ; Genes, ras ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Signal Transduction ; Cell Transformation, Neoplastic/genetics ; Mutation/genetics
    Language English
    Publishing date 2022-10-28
    Publishing country England
    Document type Review ; Journal Article
    ZDB-ID 1002702-6
    ISSN 1873-3913 ; 0898-6568
    ISSN (online) 1873-3913
    ISSN 0898-6568
    DOI 10.1016/j.cellsig.2022.110505
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: RAS pathway regulation in melanoma

    Amira Al Mahi / Julien Ablain

    Disease Models & Mechanisms, Vol 15, Iss

    2022  Volume 2

    Abstract: ... approaches aimed at drugging the RAS pathway, and outline future opportunities for therapeutic development. ... involved in the RAS pathway, highlighting recent insights into their molecular roles and diverse mechanisms ... we describe the clinical implications of RAS pathway dysregulation in melanoma, discuss past and current ...

    Abstract Activating mutations in RAS genes are the most common genetic driver of human cancers. Yet, drugging this small GTPase has proven extremely challenging and therapeutic strategies targeting these recurrent alterations have long had limited success. To circumvent this difficulty, research has focused on the molecular dissection of the RAS pathway to gain a more-precise mechanistic understanding of its regulation, with the hope to identify new pharmacological approaches. Here, we review the current knowledge on the (dys)regulation of the RAS pathway, using melanoma as a paradigm. We first present a map of the main proteins involved in the RAS pathway, highlighting recent insights into their molecular roles and diverse mechanisms of regulation. We then overview genetic data pertaining to RAS pathway alterations in melanoma, along with insight into other cancers, that inform the biological function of members of the pathway. Finally, we describe the clinical implications of RAS pathway dysregulation in melanoma, discuss past and current approaches aimed at drugging the RAS pathway, and outline future opportunities for therapeutic development.
    Keywords cancer genetics ; melanoma ; ras pathway ; signaling ; targeted therapies ; Medicine ; R ; Pathology ; RB1-214
    Subject code 570
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Understanding and drugging RAS

    Donita C. Brady / Julija Hmeljak / Arvin C. Dar

    Disease Models & Mechanisms, Vol 15, Iss

    40 years to break the tip of the iceberg

    2022  Volume 2

    Abstract: Several cancers and rare genetic diseases are caused by dysregulation in the RAS signaling pathway ... translational aspects of defining and treating RAS-driven diseases. In this Editorial, we summarize ... This Special Issue in DMM includes original Research articles on RAS-driven cancers and RASopathies ...

    Abstract Several cancers and rare genetic diseases are caused by dysregulation in the RAS signaling pathway. RAS proteins serve as molecular switches that regulate pathways involved in cellular growth, differentiation and survival. These pathways have been an intense area of investigation for four decades, since the initial identification of somatic RAS mutations linked to human cancers. In the past few years, inhibitors against several RAS effectors, as well as direct inhibitors of the K-RAS mutant G12C, have been developed. This Special Issue in DMM includes original Research articles on RAS-driven cancers and RASopathies. The articles provide insights into mechanisms and biomarkers, and evaluate therapeutic targets. Several articles also present new disease models, whereas others describe technologies or approaches to evaluate the function of RAS in vivo. The collection also includes a series of Review articles on RAS biology and translational aspects of defining and treating RAS-driven diseases. In this Editorial, we summarize this collection and discuss the potential impact of the articles within this evolving area of research. We also identify areas of growth and possible future developments.
    Keywords cancer ; developmental disorders ; ras inhibitor ; ras pathway ; Medicine ; R ; Pathology ; RB1-214
    Subject code 610
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Emerging RAS-directed therapies for cancer.

    Conroy, Michael / Cowzer, Darren / Kolch, Walter / Duffy, Austin G

    Cancer drug resistance (Alhambra, Calif.)

    2021  Volume 4, Issue 3, Page(s) 543–558

    Abstract: ... been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition ... RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers ... have seen major advances in understanding of their structure and function, including the therapeutic ...

    Abstract RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen major advances in understanding of their structure and function, including the therapeutic and prognostic significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While this has yet to be translated to everyday clinical practice, this development carries much promise. This review summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition of KRAS(G12C).
    Language English
    Publishing date 2021-04-08
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2578-532X
    ISSN (online) 2578-532X
    DOI 10.20517/cdr.2021.07
    Database MEDical Literature Analysis and Retrieval System OnLINE

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