Ras family signaling: therapeutic targeting (original) (raw)
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Targeting RAS signalling pathways in cancer therapy
Nature Reviews Cancer, 2003
RAS proteins: diversity and processing. The RAS proteins are members of a large superfamily of lowmolecular-weight GTP-binding proteins, which can be divided into several families according to the degree of sequence conservation. Different families are important for different cellular processes -the RAS family controls cell growth and the RHO family controls the actin cytoskeleton. Three members of the RAS family -HRAS, KRAS and NRAS -are found to be activated by mutation in human tumours 6 . These three members are very closely related, having 85% amino acid sequence identity and, although they function in very similar ways, some indications of subtle differences between them have recently come to light. The HRAS, KRAS and NRAS proteins are widely expressed, with KRAS being expressed in almost all cell types. Knockout studies have shown that Hras and Nras, either alone or in combination, are not required for normal development in the mouse, whereas Kras is essential 7 . This might reflect different molecular functions of the three proteins, but is more likely to reflect the more ubiquitous expression of KRAS.
Cancer Targets in the Ras Pathway
Cold Spring Harbor Symposia on Quantitative Biology, 2005
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.
Significance of Ras Signaling in Cancer and Strategies for its Control
Oncology & Hematology Review (US), 2015
Ras is a GTP-binding protein and is the most widely studied oncoprotein. To achieve its biological activity, it must undergo post-translation modification. Ras acts as a typical molecular switch. The GTP-bound Ras can activate several downstream effector pathways. Ras signaling regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. Several studies have found mutation in Ras or its effectors in various types of tumors. Therefore, Ras or its downstream effectors can be attractive drug targets against various types of tumors in cancer therapeutics. Some therapeutic agents against Ras effectors, such as Raf, MEK1/2, PI3K, AKT etc., have successfully managed to enter into phase I and II trials. This targeted drug design could be envisaged in mainly four ways, such as prevention of Ras-GTP formation, covalent locking of the GDP-bound Ras, inhibition of Ras-effector interactions, or impairment of post-translational modificati...
RAS/RAF/MEK Inhibitors in Oncology
Bentham Science
The RAS/RAF/MEK signaling pathway plays a central role in mediating both proliferation and survival of cancer cells. These proteins are a group of serine/threonine kinases activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface towards both nuclear and cytosolic targets. In combination with several other signaling pathways, they can differentially alter phosphorylation status of the transcription factors. A controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas an unregulated activation of these kinases can result in oncogenesis. Dysregulation of the RAS/RAF/MEK pathway has been detected in more than 30% of human tumors, however mutations in the MEK1 and MEK2 genes are seldom, so that hyperactivation of MEK1/2 usually results from gain-of-function mutations in RAS and/or B-RAF. In addition, alteration of the pathways is often associated with drug resistance in the clinic, such as the case of K-RAS mutant expressing tumors. Since RAS protein is a difficult target, alternative ways altering post-translational modifications using farnesyl transferase inhibitors have been adopted. Drug discovery programs have therefore largely focused on B-RAF and MEK. In this review we will discuss the most promising strategies developed to target these kinases and the most recent inhibitors facing the preclinical and clinical setting, also considering their structure-activity relationship (SAR).
Ras and Ras mutations in cancer
Central European Journal of Biology, 2013
Ras 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.
New druggable targets in the Ras pathway?
Current opinion in molecular therapeutics, 2010
Ras proteins are key elements in the regulation of cellular proliferation, differentiation and survival. Mutational activation of Ras or of components of its effector pathways are detected in one-third of human cancers and are essential for the genesis and maintenance of the tumoral phenotype. Research efforts have been dedicated to the development of therapeutic agents that inhibit aberrant Ras signals and, subsequently, tumor progression. However, many of these initiatives have proven less successful than expected. This review summarizes the current status of developments in Ras research, the challenges that have arisen during preclinical and clinical stages, and how novel approaches to targeting Ras pathways have introduced new strategies toward the development of antitumoral agents that are alternative or complementary to those currently in use. These new approaches would be aimed at disrupting key protein-protein interactions that are essential for the conveyance of Ras aberran...
Drugging the Undruggable: Advances on RAS Targeting in Cancer
Genes, 2021
Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designe...
Proceedings of the National Academy of Sciences of the United States of America, 2002
The interaction of activated Ras with Raf initiates signaling cascades that contribute to a significant percentage of human tumors, suggesting that agents that specifically disrupt this interaction might have desirable chemotherapeutic properties. We used a subtractive forward two-hybrid approach to identify small molecule compounds that block the interaction of Ras with Raf. These compounds (MCP1 and its derivatives, 53 and 110) reduced seruminduced transcriptional activation of serum response element as well as Ras-induced transcription by way of the AP-1 site. They also inhibited Ras-induced Raf-1 activation in human embryonic kidney 293 cells, Raf-1 and mitogen-activated protein kinase kinase 1 activities in HT1080 fibrosarcoma cells, and epidermal growth factor-induced Raf-1 activation in A549 lung carcinoma cells. The MCP compounds caused reversion of ras-transformed phenotypes including morphology, in vitro invasiveness, and anchorage-independent growth of HT1080 cells. Decreased level of matrix metalloproteinases was also observed. Further characterization showed that MCP compounds restore actin stress fibers and cause flat reversion in NIH 3T3 cells transformed with H-Ras (V12) but not in NIH 3T3 cells transformed with constitutively active Raf-1 (Raf⌬N). Finally, we show that MCP compounds inhibit anchorage-independent growth of A549 and PANC-1 cells harboring K-ras mutation. Furthermore, MCP110 caused G1 enrichment of A549 cells with the decrease of cyclin D level. These results highlight potent and specific effects of MCP compounds on cancer cells with intrinsic Ras activation.
Tailoring Ras-pathway—Inhibitor combinations for cancer therapy
Drug Resistance Updates, 2005
Constitutive activation of Ras pathways plays a critical role in cancer development and maintenance. Inhibitors of such pathways are already in use for cancer therapy, with significant but as yet only partial success in the most deadly types of human cancers, against which even combinations of Ras-pathway inhibitors with classic cytotoxic drugs or irradiation are insufficient. Combinations of farnesyl transferase inhibitors (FTI's), inhibitors of Ras pathways, are now in use in clinical trials. In this review we analyze possible reasons for the limited efficacy-including the diverse and sometimes even contradictory effects of active Ras pathways in tumor cells-and propose possible alternative methods of tailoring Ras-pathway inhibitor combinations for cancer therapy. Such tailoring is now possible thanks to increased knowledge of the complexity of Ras pathways, their cooperation with other oncogenic pathways, and their "addictive" nature. We provide examples demonstrating that this knowledge can be translated into useful drug combinations that disrupt multiple oncogenic pathways and hit a weak point of a given tumor cell. One such example is combination treatment with a Ras inhibitor and a glycolysis blocker for pancreatic tumor cells. The future design of such potential drug combination therapies and the follow-up of their outcome will undoubtedly be facilitated by gene-expression profiling and proteomic methods.