scholarly journals Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1535
Author(s):  
Renata Tisi ◽  
Vadim Gaponenko ◽  
Marco Vanoni ◽  
Elena Sacco
Keyword(s):  
Natural Products ◽  
Mammalian Cells ◽  
Developmental Disorders ◽  
Health Gain ◽  
Point Mutations ◽  
Ras Signaling ◽  
Cellular Processes ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Critical Issues

RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources.

Ras and Ras mutations in cancer

2013 ◽  
Vol 8 (7) ◽  
pp. 609-624 ◽  
Author(s):  
Satish Rajasekharan ◽  
Thiagarajan Raman
Keyword(s):  
Cancer Biology ◽  
Mapk Pathway ◽  
Point Mutations ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Ras Protein ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Latent Stage ◽  
Clinical Benefits

AbstractRas genes are pre-eminent genes that are frequently linked with cancer biology. The functional loss of ras protein caused by various point mutations within the gene, is established as a prognostic factor for the genesis of a constitutively active Ras-MAPK pathway leading to cancer. Ras signaling circuit follows a complex pathway, which connects many signaling molecules and cells. Several strategies have come up for targeting mutant ras proteins for cancer therapy, however, the clinical benefits remain insignificant. Targeting the Ras-MAPK pathway is extremely complicated due its intricate networks involving several upstream and downstream regulators. Blocking oncogenic Ras is still in latent stage and requires alternative approaches to screen the genes involved in Ras transformation. Understanding the mechanism of Ras induced tumorigenesis in diverse cancers and signaling networks will open a path for drug development and other therapeutic approaches.

scholarly journals The Importance of Being PI3K in the RAS Signaling Network

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1094
Author(s):  
Cristina Cuesta ◽  
Cristina Arévalo-Alameda ◽  
Esther Castellano
Keyword(s):  
Tumor Stroma ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Cellular Processes ◽  
Oncogenic Ras ◽  
Ras Activation ◽  
Fda Approval ◽  
Effector Pathway ◽  
Ras Effectors ◽  
Tumor Types

Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.

Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice

Blood ◽  
2009 ◽  
Vol 114 (17) ◽  
pp. 3629-3632 ◽  
Author(s):  
Briony A. Cutts ◽  
Anna-Karin M. Sjogren ◽  
Karin M. E. Andersson ◽  
Annika M. Wahlstrom ◽  
Christin Karlsson ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Myeloproliferative Disorders ◽  
Ras Signaling ◽  
Gtpase Activating Protein ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Ras Gtpase ◽  
Acute Myeloid

Abstract Hyperactive RAS signaling is caused by mutations in RAS genes or a deficiency of the neurofibromatosis gene (NF1) and is common in myeloid malignancies. In mice, expression of oncogenic K-RAS or inactivation of Nf1 in hematopoietic cells results in myeloproliferative disorders (MPDs) that do not progress to acute myeloid leukemia (AML). Because NF1 is a RAS-GTPase–activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. It is not clear, however, whether Nf1 deficiency would be redundant in K-RAS–induced MPD development or whether the 2 mutations would cooperate in leukemogenesis. Here, we show that the simultaneous inactivation of Nf1 and expression of K-RASG12D in mouse hematopoietic cells results in AML that was fatal in primary mice within 4 weeks and transplantable to sublethally irradiated secondary recipients. The data point to a strong cooperation between Nf1 deficiency and oncogenic K-RAS.

scholarly journals Epigenomic reprogramming of repetitive noncoding RNAs and IFN-stimulated genes by mutant KRAS

2020 ◽  
Author(s):  
Roman E. Reggiardo ◽  
Sreelakshmi Velandi Maroli ◽  
Haley Halasz ◽  
Mehmet Ozen ◽  
David Carrillo ◽  
...  
Keyword(s):  
Single Cells ◽  
Noncoding Rnas ◽  
Gene Signature ◽  
Airway Epithelial Cells ◽  
Ras Signaling ◽  
Airway Epithelial ◽  
Oncogenic Ras ◽  
Ras Genes ◽  
Lung Adenocarcinomas ◽  
Epigenomic Reprogramming

ABSTRACTRAS genes are the most frequently mutated oncogenes in cancer. However, the effects of oncogenic RAS signaling on the noncoding transcriptome are unclear. We analyzed the transcriptomes of human airway epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We found that oncogenic KRAS upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements. These repetitive noncoding RNAs exhibit differential RNA editing in single cells, are released in extracellular vesicles, and are known targets of KRAB zinc-finger proteins, which are broadly down-regulated in mutant KRAS cells and lung adenocarcinomas. Moreover, mutant KRAS induces IFN-stimulated genes through both epigenetic and RNA-based mechanisms. Our results reveal that mutant KRAS remodels the noncoding transcriptome through epigenomic reprogramming, expanding the scope of genomic elements regulated by this fundamental signaling pathway and revealing how mutant KRAS induces an intrinsic IFN-stimulated gene signature often seen in ADAR-dependent cancers.

Biology, Therapy, and Resistance of Myeloid Malignancies Initiated by Hyperactive Ras.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-9-sci-9
Author(s):  
Kevin Shannon
Keyword(s):  
Mammalian Cells ◽  
Juvenile Myelomonocytic Leukemia ◽  
Ras Signaling ◽  
Ras Proteins ◽  
Cell Fates ◽  
Myeloid Malignancies ◽  
Ras Mutations ◽  
Oncogenic Ras ◽  
Myelomonocytic Leukemia

Abstract Ras proteins regulate cell fates by cycling between active GTP-bound and inactive GDP-bound states (Ras·GTP and Ras·GDP). Ras·GTP modulates cell fates by activating effector pathways that include the Raf/MEK/ERK, phosphoinositol 3’-kinase (PI3K)/Akt, and Ral·GDS cascades. Signaling terminates when Ras·GTP is hydrolyzed to Ras·GDP. GTPase activating proteins (GAPs) are negative regulators of Ras output that increase the rate of GTP hydrolysis. Mammalian cells express two major GAPs – p120GAP and neurofibromin. The latter is encoded by the NF1 tumor suppressor gene, which is mutated in persons with neurofibromatosis type 1 (NF1). Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML) and other cancers. Somatic RAS mutations are also common in myeloid malignancies, and other leukemia-associated mutations, such as FLT3 internal tandem duplications, PTPN11 point mutations, and the BCR-ABL fusion protein deregulate Ras signaling. Together, the prevalence of oncogenic RAS mutations and the existence of these alternative genetic mechanisms establish hyperactive Ras as a major therapeutic target. However, developing inhibitors of oncogenic Ras proteins is extremely challenging due to structural considerations and because an effective drug must restore normal biochemical activity (i.e., repair a broken enzyme). Strains of mice carrying conditional mutant alleles of Nf1, oncogenic Kras, and oncogenic Nras are novel reagents for understanding how cells remodel signaling networks in response to hyperactive Ras and for performing pre-clinical trials. Use of the Mx1-Cre transgene to ablate Nf1 or to activate oncogenic KrasG12D or NrasG12D expression in hematopoietic cells causes myeloproliferative disorders (MPDs) that model JMML and chronic myelomonocytic leukemia (CMML). We are using retroviral insertional mutagenesis (RIM) to identify cooperating mutations that might induce progression from MPD to acute myeloid leukemia (AML). CI-1040, a potent inhibitor of MEK, unexpectedly had no beneficial effects in Nf1 mutant mice with MPD. By contrast, MEK inhibition induced regression of Nf1-deficient AMLs. These AMLs uniformly developed resistance in vivo, despite equivalent biochemical inhibition of the target in paired sensitive and resistant clones. Analysis of retroviral insertions in resistant AMLs revealed outgrowth of a pre-existing clone during CI-1040 administration, and we have implicated RasGRP1 and p38α as modulating resistance in vivo. These data emphasize the importance of cell context in the response to targeted agents and establish a tractable in vivo system for identifying genes that modulate therapeutic efficacy and for probing mechanisms of acquired resistance.

scholarly journals Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Patrick D. Rädler ◽  
Barbara L. Wehde ◽  
Aleata A. Triplett ◽  
Hridaya Shrestha ◽  
Jonathan H. Shepherd ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Epithelial Cells ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Ras Signaling ◽  
Preneoplastic Lesions ◽  
Independent Manner ◽  
Oncogenic Ras ◽  
Luminal Epithelial Cells

AbstractClaudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

AbstractBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

Dampening oncogenic RAS signaling

Science ◽  
2019 ◽  
Vol 363 (6433) ◽  
pp. 1280-1281 ◽  
Author(s):  
Trever G. Bivona
Keyword(s):  
Ras Signaling ◽  
Oncogenic Ras
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