KRAS mutations predict response to EGFR inhibitors
ABSTRACT Five antiepidermal growth factor receptor therapies have been approved for the treatment of solid tumors. However, response rates are relatively low. Several biomarkers that enrich for patients with tumors most likely to respond to these therapeutic agents have been identified. Mutations in the intermediate signal transduction pathway member KRAS also selects patients with tumors depending on signaling through this pathway. However, because KRAS acts downstream of the EGF receptor, somatic changes in this gene can be used as a marker to exclude patients unlikely to benefit from anti-EGFR therapy. Recent clinical data have provided substantial evidence that KRAS mutational status should be utilized as a diagnostic marker for predicting that response to anti-EGFR therapies in colorectal and non-small cell lung cancer.
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ABSTRACT: Pancreatic cancer has the worst five-year survival rate of all malignancies due to its aggressive progression and resistance to therapy. Current therapies are limited to gemcitabine-based chemotherapeutics, surgery, and radiation. The current trend toward "personalized genomic medicine" has the potential to improve the treatment options for pancreatic cancer. Gene identification and genetic alterations like single nucleotide polymorphisms and mutations will allow physicians to predict the efficacy and toxicity of drugs, which could help diagnose pancreatic cancer, guide neoadjuvant or adjuvant treatment, and evaluate patients' prognosis. This article reviews the multifaceted roles of genomics and pharmacogenomics in pancreatic cancer. Copyright © 2015. Published by Elsevier Ireland Ltd.Cancer letters 04/2015; 363(1). DOI:10.1016/j.canlet.2015.04.009 · 5.02 Impact Factor
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ABSTRACT: KRAS codons 12 and 13 mutations are commonly used to identify colorectal carcinoma (CRC) patients who are unlikely to benefit from anti-EGFR therapy. However, humans have four different homologous RAS proteins and no routine screening is performed for the other mutation sites. Non-screened mutations may still be present in a significant subset of patients without KRAS codon 12 and 13 mutations. We developed a LightCycler screening assay that encompasses codons 12, 13 and 61 of all RAS genes. Screen-positive specimens were characterized by Sanger sequencing. 130 CRC specimens were screened for all RAS genes. The results for KRAS codons 12 and 13 were compared with an FDA approved method (Qiagen). Twenty-nine of 130 specimens (22.3%) were positive for KRAS codons 12 and 13, with 100% congruence with the Qiagen method. Six additional specimens were identified to have mutations. One mutation in HRAS codon 61, two in KRAS codon 61, and three in NRAS codon 61. Limiting RAS testing to only KRAS codons 12 and 13 in companion diagnostic testing of CRC results in nearly 1/5th of patients with RAS mutations not being excluded from costly EGFR antagonist treatment, despite likely futility. Inclusion of all RAS genes in companion diagnostic screening is warranted.Clinica chimica acta; international journal of clinical chemistry 07/2013; 425. DOI:10.1016/j.cca.2013.06.025 · 2.76 Impact Factor
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ABSTRACT: Chordoma is a rare malignant bone tumour, showing notochordal differentiation, which occurs in the axial skeleton. Brachyury, a molecule involved in notochordal development, is a highly specific and sensitive marker for chordoma. It is hypothesised that brachyury or genes involved in its activation are implicated in the pathogenesis of chordoma. As there is currently no effective drug therapy for chordoma the aim of this study was to identify genetic events involved in chordoma pathogenesis with a view to identifying potential therapeutic targets. One hundred chordomas (50 skull-based, 50 non-skull based) were studied. Immunohistochemistry showed that the PI3K/AKT/TSC/mTOR pathway was activated in 65% of chordomas, thereby providing a rationale for testing mTOR inhibitors for the treatment of selected cases. DNA sequencing revealed no mutations in PI3KCA or RAS homologue enriched in brain (Rheb) in 23 tumours. Immunohistochemistry and Western blotting showed activation of the fibroblastic growth factor receptor (FGFR)/RAS/RAF/MEK/ERK/ETS2/brachyury pathway in more than 90% of cases, but no mutations were found in the genes analysed (FGFRs, KRAS, BRAF and brachyury) in 23 tumours. Three percent of cases revealed brachyury amplification but nearly half of the cases showed chromosomal abnormalities involving the brachyury locus. Knockdown of brachyury was achieved in the U-CH1 chordoma cell line using shRNA and resulted in premature cell senescence. These findings demonstrate that brachyury plays an important role in chordoma pathology. FISH analysis showed EGFR copy number gain in 45% of chordomas, including 6% with amplification and 39% with high level polysomy. The EGFR inhibitor, tyrphostin (AG1478) significantly inhibited growth of the chordoma cell line, and Western blotting showed this was associated with reduced phosphorylation of EGFR in a dose dependent manner. This study provides evidence for the first time that selected chordomas may be susceptible to treatment with EGFR inhibitors.