Therapeutic Strategies for Targeting Ras Proteins

UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Genes & cancer 03/2011; 2(3):359-72. DOI: 10.1177/1947601911412376
Source: PubMed

ABSTRACT Ras genes are frequently activated in cancer. Attempts to develop drugs that target mutant Ras proteins have, so far, been unsuccessful. Tumors bearing these mutations, therefore, remain among the most difficult to treat. Most efforts to block activated Ras have focused on pathways downstream. Drugs that inhibit Raf kinase have shown clinical benefit in the treatment of malignant melanoma. However, these drugs have failed to show clinical benefit in Ras mutant tumors. It remains unclear to what extent Ras depends on Raf kinase for transforming activity, even though Raf proteins bind directly to Ras and are certainly major effectors of Ras action in normal cells and in development. Furthermore, Raf kinase inhibitors can lead to paradoxical activation of the MAPK pathway. MEK inhibitors block the Ras-MAPK pathway, but often activate the PI3'-kinase, and have shown little clinical benefit as single agents. This activation is mediated by EGF-R and other receptor tyrosine kinases through relief of a negative feedback loop from ERK. Drug combinations that target multiple points within the Ras signaling network are likely to be necessary to achieve substantial clinical benefit. Other effectors may also contribute to Ras signaling and provide a source of targets. In addition, unbiased screens for genes necessary for Ras transformation have revealed new potential targets and have added to our understanding of Ras cancer biology.

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    • "The screening also highlighted that silencing of individual genes involved in RAS signaling is ineffective on suppressing the growth of KRAS mutant CRC cells. This suggests that RAS controls a largely redundant signaling network, which guarantees that interference with an individual effector does not interrupt pathway output (Cox and Der, 2010; Gysin et al., 2011 "
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    Cell Reports 09/2014; 8(5). DOI:10.1016/j.celrep.2014.07.033 · 8.36 Impact Factor
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    • "Overall, there were no large differences between groups. Some parallels might be drawn, such as the key processes of cognitive performance in NF1 as in typical elderly might be the result of myelin dysfunction [Goh, 2011; Gutmann et al., 1997; Gysin et al., 2011; Lu et al., 2013; Mayes et al., 2013 Sep 11; Payne et al., 2010]. Additionally, at the molecular level, some animal model based studies have shown NF1 deficits in hippocampal long-term potentiation (LTP) due to changes in GABA inhibition, which is a crucial mechanism to spatial learning and memory [Silva et al., 1997]. "
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    • "These findings clearly demonstrate the role of inflammation in the development of PDAC. As all attempts of developing a drug that directly blocks the mutated K-Ras oncogene has been unsuccessful [28], did we target downstream factors activated by K-Ras. The signaling cascades through K-Ras lead to many different events inside the cell and several pathways, i.e. "
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    ABSTRACT: The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.
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