Cancer Targets in the Ras Pathway

Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, 94115, USA.
Cold Spring Harbor Symposia on Quantitative Biology 02/2005; 70:461-7. DOI: 10.1101/sqb.2005.70.044
Source: PubMed


Ras proteins play a direct causal role in human cancer and in other diseases. Mutant H-Ras, N-Ras, and K-Ras occur in varying frequencies in different tumor types, for reasons that are not known. Other members of the Ras superfamily may also contribute to cancer. Mutations also occur in downstream pathways, notably B-Raf, PTEN, and PI 3' kinase: These pathways interact at multiple points, including cyclin D1, and act synergistically. In some cases mutations in Ras and effectors are mutually exclusive; in other cases, they coexist. Drugs blocking elements of the pathway are in different stages of clinical development. One of these, the Raf kinase/VEGF-R2 inhibitor Sorafenib, has already been approved for treatment of renal cancer and is being tested in other indications. However, therapeutic targets in the Ras pathway have not yet been fully validated as bona fide targets.

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Available from: Osamu Tetsu, Mar 16, 2015
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    • "In the setting of cancer, mutations in RAS maintain RAS in its activated state and drive persistent proliferation and survival of transformed cells via one or more effector pathways. As a central mediator of multiple signaling pathways, pharmacologic inhibition of RAS, its post-translational modification, or its downstream effector proteins has been widely pursued as a potential treatment for cancer (Bollag et al., 2010; Downward, 2003; Rodriguez-Viciana et al., 2005). "
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    ABSTRACT: Activating mutations in the KRAS oncogene are associated with three related human syndromes, which vary in hair and skin phenotypes depending on the involved allele. How variations in RAS signals are interpreted during hair and skin development is unknown. In this study, we investigated the developmental and transcriptional response of skin and hair to changes in RAS activity, using mouse genetic models and microarray analysis. While activation of Kras (Kras(G12D)) in the skin had strong effects on hair growth and hair shape, steady state changes in downstream RAS/MAPK effectors were subtle and detected only by transcriptional responses. To model the transcriptional response of multiple developmental pathways to active RAS, the effects of growth factor stimulation were studied in skin explants. Here FGF acutely suppressed Shh transcription within 90 minutes but had significantly less effect on Eda, WNT, Notch or BMP pathways. Furthermore, in vivo Fgfr2 loss-of-function in the ectoderm caused derepression of Shh, revealing a role for FGF in Shh regulation in the hair follicle. These studies define both dosage sensitive effects of RAS signaling on hair morphogenesis and reveal acute mechanisms for fine-tuning Shh levels in the hair follicle.
    Developmental Biology 10/2012; 373(2). DOI:10.1016/j.ydbio.2012.10.024 · 3.55 Impact Factor
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    • "Two of them (p53 and p53 hypoxia) are directly linked to p53. Others have obvious links to tumorigenesis, such as the RAS pathway [28], which is also well understood to be related to p53 expression regulation [17]. The significant G1 & S phase pathway contains members that regulate the progression through G1-S phases of the cell cycle, such as CDK2 and CDK4 [29]. "
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    ABSTRACT: The molecular behavior of biological systems can be described in terms of three fundamental components: (i) the physical entities, (ii) the interactions among these entities, and (iii) the dynamics of these entities and interactions. The mechanisms that drive complex disease can be productively viewed in the context of the perturbations of these components. One challenge in this regard is to identify the pathways altered in specific diseases. To address this challenge, Gene Set Enrichment Analysis (GSEA) and others have been developed, which focus on alterations of individual properties of the entities (such as gene expression). However, the dynamics of the interactions with respect to disease have been less well studied (i.e., properties of components ii and iii). Here, we present a novel method called Gene Interaction Enrichment and Network Analysis (GIENA) to identify dysregulated gene interactions, i.e., pairs of genes whose relationships differ between disease and control. Four functions are defined to model the biologically relevant gene interactions of cooperation (sum of mRNA expression), competition (difference between mRNA expression), redundancy (maximum of expression), or dependency (minimum of expression) among the expression levels. The proposed framework identifies dysregulated interactions and pathways enriched in dysregulated interactions; points out interactions that are perturbed across pathways; and moreover, based on the biological annotation of each type of dysregulated interaction gives clues about the regulatory logic governing the systems level perturbation. We demonstrated the potential of GIENA using published datasets related to cancer. We showed that GIENA identifies dysregulated pathways that are missed by traditional enrichment methods based on the individual gene properties and that use of traditional methods combined with GIENA provides coverage of the largest number of relevant pathways. In addition, using the interactions detected by GIENA, specific gene networks both within and across pathways associated with the relevant phenotypes are constructed and analyzed.
    BMC Systems Biology 06/2012; 6(1):65. DOI:10.1186/1752-0509-6-65 · 2.44 Impact Factor
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    • "Activated Ras interacts with several effector proteins in ways that stimulate catalytic activities, and it also controls the activity of crucial signaling that regulates normal cellular proliferation [3]. Mutations in downstream targets of Ras signaling, such as v-raf murine sarcoma viral oncogene homolog B1 (B-Raf), phosphatase and tensin homolog (PTEN), and phosphatidylinositol 3-kinase (PI3K), were discovered through studies of mutated Ras [4]. Ras is a low-molecular-weight GTP/GDP binding GTPase that activates two major pathways that are deduced to play a critical role in human cancer progression [5]: 1) the PI3K/Akt pathway, and 2) the mitogen-activated Mek/extracellular signal-related kinase (Erk) pathway. "
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    ABSTRACT: We synthesized novel aliphatic amido-quaternary ammonium salts in an effort to discover anticancer agents that increase Ras homolog gene family, member B, (RhoB) levels. These compounds exert anti-proliferative activities against several human cancer cell types. Seventeen compounds, varying in aliphatic carbon chain length and N-substituents, were synthesized and their biological activities were evaluated. Of these 17 compounds, compound 3i emerged as the most promising anticancer compound by promoting apoptosis through the RhoB mediated pathway. Potent biological activities observed for these novel aliphatic amido-quaternary ammonium salt analogues support their potential as anticancer, chemotherapeutic agents.Graphical abstractA series of aliphatic amido-quaternary ammonium salts were designated, synthesized and evaluated for anticancer chemotherapy. Compound 3i was emerged as the most promising anticancer compound promoting apoptosis through RhoB mediated pathway.Highlights►17 Novel aliphatic amido-quaternary ammonium salts were synthesized and evaluated.►3c, 3f, and 3i showed better in vitro activity than the lead compound.►3i emerged as the most promising agent through RhoB mediated pathway.►Anti-proliferative activity is significantly related to the RhoB activation.►These compounds could be promising anticancer agents for anticancer chemotherapy.
    European Journal of Medicinal Chemistry 07/2011; 46(7):2861-2866. DOI:10.1016/j.ejmech.2011.04.009 · 3.45 Impact Factor
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