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

ABSTRACT 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.

Download full-text


Available from: Osamu Tetsu, Mar 16, 2015
1 Follower
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 3.64 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.43 Impact Factor
  • Source
    • "In fact, mutations in the downstream signaling elements often amplify the transmission of messages from RTKs. Because oncogenic mutations are frequently found in HRAS, KRAS, NRAS, and BRAF in the MAPK pathway as well as in PIK3CA and PTEN in the PI3K/Akt cascade, we searched for mutations in these genes [14]. Table 2 shows primer sets used to detect oncogenic mutations in these genes and our exons of focus. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.
    Neoplasia (New York, N.Y.) 09/2010; 12(9):708-17. DOI:10.1593/neo.10356 · 5.40 Impact Factor
Show more