Article

The KRAS oncogene: Past, present, and future

Department of Surgery, University Medical Center Utrecht, Utrecht.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 12/2005; 1756(2):81-2. DOI: 10.1016/j.bbcan.2005.10.001
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    • "For example, the gene encoding the RTK neu/HER2 is amplified in ~30% of breast cancer cases and the RTK EGFR is mutated in ~25% of non small cell lung carcinoma patients (Hynes and MacDonald, 2009; Mitri et al., 2012). Activating mutations in Ras are prevalent in pancreatic (~95%), thyroid (55%), colorectal (35%) and lung (35%) carcinomas and in myeloid leukemia (30%) (Bos, 1989; Kranenburg, 2005). The gene encoding the B-Raf kinase is mutated in about 40% (in some reports 80%) of melanoma cases (Pollock and Meltzer, 2002; Pollock et al., 2003). "
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    ABSTRACT: The Receptor-Tyrosine Kinase(RTK)/Ras/Raf pathway is an essential cascade for mediating growth factor signaling. It is abnormally overactive in almost all human cancers. The downstream targets of the pathway are members of the Extracellular Regulated Kinases (Erk1/2) family, suggesting that this family is a mediator of the oncogenic capability of the cascade. Although all oncogenic mutations in the pathway result in strong activation of Erks, activating mutations in Erks themselves were not reported in cancers. Here we used spontaneously active Erk variants to check whether Erk's activity per se is sufficient for oncogenic transformation. We show that Erk1(R84S) is an oncoprotein as NIH3T3 cells that express it form foci in tissue culture plates, colonies in soft agar and tumors in nude mice. We further show that Erk1(R84S) and Erk2(R65S) are intrinsically active due to an unusual autophosphorylation activity they acquired. They autophosphorylate the activatory TEY motif, and also other residues, including the critical residue Thr207 (in Erk1)/Thr188 (in Erk2). Strikingly, Erk2(R65S) is efficiently autophosphorylating its Thr188 even when dually mutated in the TEY motif. Thus, this study shows that Erk1 can be considered a proto-oncogene and that Erk molecules possess unusual autoregulatory properties, some of them are independent of TEY phosphorylation.
    Preview · Article · Dec 2015 · Molecular Biology of the Cell
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    • "A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma (Kranenburg, 2005). "
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    ABSTRACT: Cell-free nucleic acids (CFNA) have been reported by several authors in blood, stool, and urine of patients with colorectal cancer (CRC). These genetic biomarkers can be an indication of neoplastic colorectal epithelial cells, and can thus potentially be used as noninvasive tests for the detection of the disease in CRC patients and monitor their staging, without the need to use heavier and invasive tools. In a number of test-trials, these genetic tests have shown the advantage of non-invasiveness, making them well accepted by most of the patients, without major side effects. They have also shown a promising sensitivity and specificity in the detection of malignant and premalignant neoplasms. Moreover, costs for performing such tests are very low. Several studies reported and confirmed the proof of the principle for these genetic tests for screening, diagnosis, and prognosis; the main challenge of translating this approach from research to clinical laboratory is the validation from large and long-term randomized trials to prove sustainable high sensitivity and specificity. In this paper, we present a review on the noninvasive genetics biomarkers for CRC detection described in the literature and the challenges that can be encountered for validation processes.
    Full-text · Article · Aug 2014 · Frontiers in Genetics
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    • "The 73 cancer amplified genes included a number of receptor tyrosine kinases, GTPases, adaptors and signaling genes in the MAP kinase pathway. One of the most important amplified genes is the proto-oncogene KRAS, a small GTPase that is frequently mutated in lung, pancreatic and colorectal cancers [24]. A single amino acid substitution in KRAS results in activating mutation and dependence of the cancer cells on the MAP kinase pathway. "
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    ABSTRACT: The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways activated across cancer types. Analysis of TCGA datasets have mostly focused on somatic mutations and translocations, with less emphasis placed on gene amplifications. Here we describe a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets. We carried out GISTIC2 analysis of TCGA datasets spanning 16 cancer subtypes and identified 486 genes that were amplified in two or more datasets. The list was narrowed to 75 cancer-associated genes with potential "druggable" properties. The majority of the genes were localized to 14 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 42 putative cancer driver genes linked to diverse oncogenic processes. Oncogenic activity was further validated by siRNA/shRNA knockdown and by referencing the Project Achilles datasets. The amplified genes represented a number of gene families, including epigenetic regulators, cell cycle-associated genes, DNA damage response/repair genes, metabolic regulators, and genes linked to the Wnt, Notch, Hedgehog, JAK/STAT, NF-KB and MAPK signaling pathways. Among the 42 putative driver genes were known driver genes, such as EGFR, ERBB2 and PIK3CA. Wild-type KRAS was amplified in several cancer types, and KRAS-amplified cancer cell lines were most sensitive to KRAS shRNA, suggesting that KRAS amplification was an independent oncogenic event. A number of MAP kinase adapters were co-amplified with their receptor tyrosine kinases, such as the FGFR adapter FRS2 and the EGFR family adapters GRB2 and GRB7. The ubiquitin-like ligase DCUN1D1 and the histone methyltransferase NSD3 were also identified as novel putative cancer driver genes. We discuss the patient tailoring implications for existing cancer drug targets and we further discuss potential novel opportunities for drug discovery efforts.
    Full-text · Article · May 2014 · PLoS ONE
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