Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Biology, pathology, and therapeutic targeting of RAS.

ABSTRACT: RAS was identified as a human oncogene in the early 1980s and subsequently found to be mutated in nearly 30% of all human cancers. More importantly, RAS plays a central role in driving tumor development and maintenance. Despite decades of effort, there remain no FDA approved drugs that directly inhibit RAS. The prevalence of RAS mutations in cancer and the lack of effective anti-RAS therapies stem from RAS' core role in growth factor signaling, unique structural features, and biochemistry. However, recent advances have brought promising new drugs to clinical trials and shone a ray of hope in the field. Here, we will exposit the details of RAS biology that illustrate its key role in cell signaling and shed light on the difficulties in therapeutically targeting RAS. Furthermore, past and current efforts to develop RAS inhibitors will be discussed in depth.

SUBMITTER: Rhett JM

PROVIDER: S-EPMC7393484 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Biology, pathology, and therapeutic targeting of RAS.

Rhett J Matthew JM Khan Imran I O'Bryan John P JP

Advances in cancer research 20200709

RAS was identified as a human oncogene in the early 1980s and subsequently found to be mutated in nearly 30% of all human cancers. More importantly, RAS plays a central role in driving tumor development and maintenance. Despite decades of effort, there remain no FDA approved drugs that directly inhibit RAS. The prevalence of RAS mutations in cancer and the lack of effective anti-RAS therapies stem from RAS' core role in growth factor signaling, unique structural features, and biochemistry. Howev ...[more]

PMID: 32723567

Similar Datasets

Promoter hypermethylation in MLL-r leukemia: biology and therapeutic targeting

Project description:MLL-r infant acute lymphoblastic leukemia (ALL) has largely unclear oncogenesis. It has been shown unrelated to copy number change or mutations in the tyrosine kinome. We therefore, explored the possible role of genome wide CpG island hypermethylation in MLL-r infant ALL. We employed the HpaII-tiny fragment Enrichment by Ligation-mediated PCR (HELP) assay to examine MLL-r infant leukemia samples (n=5), other common childhood ALL (n=5) and normals (n=5). We then investigated biological correlation and the therapeutic potential of 5-aza-2’-deoxycytidine (decitabine). Analysis of the HELP assay showed both tight clustering of samples into their biological groups and that MLL-r infant leukemia was globally and comparatively hypermethylated. Further, a majority of genes chosen for analysis from the HELP assay were silenced or under-expressed. MLL-r cell lines showed dose and time-dependent cell kill when treated with decitabine and most down-regulated genes showed increase in expression. This was not seen in the MLL-wt cell line. For the re-expressed genes, methylation specific PCR confirmed preferential promoter methylation in MLL-r samples. Together, this suggests that methylation signatures are unique in pediatric ALL, that promoter hypermethylation may play a significant role in MLL-r infant leukemogenesis, that this can be reversed and demethylating agents may be a potential new therapeutic option in infant leukemia. Keywords: DNA methylation profiling Direct comparison of DNA methylation in leukemic blasts from 5 infants with MLL-r ALL with 5 children with other common types of ALL and 5 normal samples consisting of CD34+ selected cord blood cells (n=3) and CD19+ selected cord blood cells (n=2)

2009-12-29 | E-GEOD-19671 | biostudies-arrayexpress

Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families.

Project description:Allosteric mechanisms are pervasive in nature, but human-designed allosteric perturbagens are rare. The history of KRASG12C inhibitor development suggests that covalent chemistry may be a key to expanding the armamentarium of allosteric inhibitors. In that effort, irreversible targeting of a cysteine converted a non-deal allosteric binding pocket and low affinity ligands into a tractable drugging strategy. Here we examine the feasibility of expanding this approach to other allosteric pockets of RAS and kinase family members, given that both protein families are regulators of vital cellular processes that are often dysregulated in cancer and other human diseases. Moreover, these heavily studied families are the subject of numerous drug development campaigns that have resulted, sometimes serendipitously, in the discovery of allosteric inhibitors. We consequently conducted a comprehensive search for cysteines, a commonly targeted amino acid for covalent drugs, using AlphaFold-generated structures of those families. This new analysis presents potential opportunities for allosteric targeting of validated and understudied drug targets, with an emphasis on cancer therapy.

| S-EPMC9590303 | biostudies-literature

Therapeutic targeting of RAS: New hope for drugging the "undruggable".

Project description:RAS is the most frequently mutated oncogene in cancer and a critical driver of oncogenesis. Therapeutic targeting of RAS has been a goal of cancer research for more than 30 years due to its essential role in tumor formation and maintenance. Yet the quest to inhibit this challenging foe has been elusive. Although once considered "undruggable", the struggle to directly inhibit RAS has seen recent success with the development of pharmacological agents that specifically target the KRAS(G12C) mutant protein, which include the first direct RAS inhibitor to gain entry to clinical trials. However, the limited applicability of these inhibitors to G12C-mutant tumors demands further efforts to identify more broadly efficacious RAS inhibitors. Understanding allosteric influences on RAS may open new avenues to inhibit RAS. Here, we provide a brief overview of RAS biology and biochemistry, discuss the allosteric regulation of RAS, and summarize the various approaches to develop RAS inhibitors.

| S-EPMC6937383 | biostudies-literature

Biology and therapeutic targeting of molecular mechanisms in MPNs.

Project description:Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription signaling. As a result, JAK inhibitors have been the standard therapy for treatment of patients with myelofibrosis (MF). Although currently approved JAK inhibitors successfully ameliorate MPN-related symptoms, they are not known to substantially alter the MF disease course. Similarly, in essential thrombocythemia and polycythemia vera, treatments are primarily aimed at reducing the risk of cardiovascular and thromboembolic complications, with a watchful waiting approach often used in patients who are considered to be at a lower risk for thrombosis. However, better understanding of MPN biology has led to the development of rationally designed therapies, with the goal of not only addressing disease complications but also potentially modifying disease course. We review the most recent data elucidating mechanisms of disease pathogenesis and highlight emerging therapies that target MPN on several biologic levels, including JAK2-mutant MPN stem cells, JAK and non-JAK signaling pathways, mutant calreticulin, and the inflammatory bone marrow microenvironment.

| S-EPMC10163317 | biostudies-literature

Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers.

Project description:In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.

| S-EPMC9454753 | biostudies-literature

The complex landscape of microRNAs in articular cartilage: biology, pathology, and therapeutic targets.

Project description:The disabling degenerative disease osteoarthritis (OA) is prevalent among the global population. Articular cartilage degeneration is a central feature of OA; therefore, a better understanding of the mechanisms that maintain cartilage homeostasis is vital for developing effective therapeutic interventions. MicroRNAs (miRs) modulate cell signaling pathways and various processes in articular cartilage via posttranscriptional repression of target genes. As dysregulated miRs frequently alter the homeostasis of articular cartilage, modulating select miRs presents a potential therapeutic opportunity for OA. Here, we review key miRs that have been shown to modulate cartilage-protective or -destructive mechanisms and signaling pathways. Additionally, we use an integrative computational biology approach to provide insight into predicted miR gene targets that may contribute to OA pathogenesis, and highlight the complexity of miR signaling in OA by generating both unique and overlapping gene targets of miRs that mediate protective or destructive effects. Early OA detection would enable effective prevention; thus, miRs are being explored as diagnostic biomarkers. We discuss these ongoing efforts and the applicability of miR mimics and antisense inhibitors as potential OA therapeutics.

| S-EPMC6171796 | biostudies-literature

Promoter hypermethylation in MLL-r leukemia: biology and therapeutic targeting

2009-12-29 | GSE19671 | GEO

IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting.

Project description:Over 20 years ago, it was first proposed that autoinflammation underpins a handful of rare monogenic disorders characterized by recurrent fever and systemic inflammation. The subsequent identification of novel, causative genes directly led to a better understanding of how the innate immune system is regulated under normal conditions, as well as its dysregulation associated with pathogenic mutations. Early on, IL-1 emerged as a central mediator for these diseases, based on data derived from patient cells, mutant mouse models and definitive clinical responses to IL-1 targeted therapy. Since that time, our understanding of the mechanisms of autoinflammation has expanded beyond IL-1 to additional innate immune processes. However, the number and complexity of IL-1-mediated autoinflammatory diseases has also multiplied to include additional monogenic syndromes with expanded genotypes and phenotypes, as well as more common polygenic disorders seen frequently by the practising clinician. In order to increase physician awareness and update rheumatologists who are likely to encounter these patients, this review discusses the general pathophysiological concepts of IL-1-mediated autoinflammation, the epidemiological and clinical features of specific diseases, diagnostic challenges and approaches, and current and future perspectives for therapy.

| S-EPMC9210802 | biostudies-literature

Methyltransferase-like proteins in cancer biology and potential therapeutic targeting.

Project description:RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.

| S-EPMC10394802 | biostudies-literature

The bone marrow microenvironment and leukemia: biology and therapeutic targeting.

Project description:Multiple studies have demonstrated that interaction with the bone marrow stromal microenvironment contributes to the survival of leukemia cells. One explanation for this phenomenon is the interaction between the cell surface receptors CXCR4 and CXCL12. Through CXCL12/CXCR4-mediated chemotaxis, leukemia cells migrate to microscopic niches within the bone marrow, which leads to increased proliferation and survival. Several studies have suggested that increased CXCR4 expression may portend a poor prognosis in various types of leukemia, possibly due to increased protection of leukemia cells by bone marrow stroma. A potential therapeutic strategy to overcome this stromal-mediated survival advantage is to target CXCR4. Inhibition of CXCR4 may allow leukemia cells to be released from bone marrow niches that confer resistance to chemotherapy and negate the survival benefit imparted by bone marrow stroma.

| S-EPMC3131221 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data