Abstract
The prevalence of oncogenic rat sarcoma virus (RAS) mutations has made RAS a popular target for cancer therapies. Significant discoveries have been reported regarding cancer molecular biology following the study of RAS mutations. These discoveries are integral in shaping the era of targeted cancer therapy, with direct targeting of RAS or downstream RAS effectors, such as Grb2 and MAPK a possibility. Novel agents such as farnesyltransferase directly bind and sequester RAS. While these new agents and approaches have shown promise in preclinical and clinical studies, the complexity of RAS signaling and the potential for robust adaptive feedback continue to present substantial challenges. Therefore, the development of targeted therapies will require a detailed understanding of the properties and dependencies of specific cancers to a RAS mutation. This review provides an overview of RAS mutations and their relationship with cancer and discusses their potential as therapeutic targets.
Highlights
Personalized medicine allows for the treatment of patient by optimizing therapeutic outcome and lowering toxicity
The latest advances in the understanding of RAS biology have led to new opportunities for directly targeting RAS or to more effectively target key RAS effectors
The development of targeted therapies will require a detailed understanding of the properties and dependencies of specific cancer to RAS mutation
Summary
RASA3, which is a Ras-GTPase activating gene located at the plasma membrane close to RAS, has been shown to cause various cancers in mice and humans when it is inactivated, causing a buildup of active RAS-GTP [16] These cancers include glioblastoma, squamous-cell carcinoma and abdominal cavity sarcoma. RAS is a small guanine nucleotidebinding protein that regulates the state of signal transduction pathways central to cell growth, proliferation and survival [25,26] It switches between active and inactive signaling states, depending on if it is in GTP- or GDP-bound state, respectively. One study has demonstrated that the combination of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as well as MEK inhibitors is an effective drug combination therapy [8] Both inhibitors function harmoniously to induce cellular apoptosis in tumors exhibiting RAS mutations. Tipifarnib, approved by the US FDA for the treatment of elderly acute leukemia, is a Ras pathway inhibitor [35]
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