Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab
ABSTRACT The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab.
One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies.
Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively).
Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.
- SourceAvailable from: Wei Chen
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- "This is our next plan and will be a long-range research and the results we get will be very valuable for the clinic. Khambata-Ford et al. demonstrated that DUSP4 is one of the top drug resistance markers in metastatic colorectal cancer patients . Lung cancer patients with EGFR mutations respond well to Cetuximab, and it was recently shown that DUSP4 is downregulated in lung cancers with EGFR mutations . "
ABSTRACT: Breast cancer is the major cause of cancer-related deaths in females world-wide. Doxorubicin-based therapy has limited efficacy in breast cancer due to drug resistance, which has been shown to be associated with the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms linking the EMT and drug resistance in breast cancer cells remain unclear. Dual specificity phosphatase 4 (DUSP4), a member of the dual specificity phosphatase family, is associated with cellular proliferation and differentiation; however, its role in breast cancer progression is controversial. We used cell viability assays, Western blotting and immunofluorescent staining, combined with siRNA interference, to evaluate chemoresistance and the EMT in MCF-7 and adriamycin-resistant MCF-7/ADR breast cancer cells, and investigate the underlying mechanisms. Knockdown of DUSP4 significantly increased the chemosensitivity of MCF-7 and MCF-7/ADR breast cancer cells to doxorubicin, and MCF-7/ADR cells which expressed high levels of DUSP4 had a mesenchymal phenotype. Furthermore, knockdown of DUSP4 reversed the EMT in MCF-7/ADR cells, as demonstrated by upregulation of epithelial biomarkers and downregulation of mesenchymal biomarkers, and also increased the chemosensitivity of MCF-7/ADR cells to doxorubicin. DUSP4 might represent a potential drug target for inhibiting drug resistance and regulating the process of the EMT during the treatment of breast cancer.Experimental Cell Research 09/2013; 319(20). DOI:10.1016/j.yexcr.2013.08.023 · 3.37 Impact Factor
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- "Finally, recent studies have shown that high levels of expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with response to anti-EGFR MoAbs in CRC patients [Khambata-Ford et al., 2007; Jacobs et al., 2009]. These data suggest that in CRC the regulation of downstream EGFR signaling pathways depends mainly on AREG and EREG binding to ErbB receptors in KRAS wild-type patients. "
ABSTRACT: Increasing evidence demonstrates that target based-agents are active only in molecularly selected populations of patients. Therefore, the identification of predictive biomarkers has become mandatory to improve the clinical development of these novel drugs. Mutations of the epidermal growth factor receptor (EGFR) or rearrangements of the ALK gene in non-small-cell lung cancer, and BRAF mutations in melanoma are clear examples of driver mutations and predictive biomarkers of response to treatment with specific inhibitors. Predictive biomarkers might also identify subgroups of patients that are not likely to respond to specific drugs, as shown for KRAS mutations and anti-EGFR monoclonal antibodies in colorectal carcinoma. The discovery of novel driver molecular alterations and the availability of drugs capable to selectively block such oncogenic mechanisms is leading to a rapid increase in the number of putative biomarkers that need to be assessed in each single patient. In this respect, two different approaches are being developed to introduce a comprehensive molecular characterization in clinical practice: high throughput genotyping platforms, which allow the detection of recognized genetic aberrations in clinical samples, and next generation sequencing that can provide information on all the different types of cancer-causing alterations. The introduction of these techniques in clinical practice will increase the possibility to identify molecular targets in each individual patient, and will also allow to follow the molecular evolution of the disease during the treatment. By using these approaches the development of personalized medicine for cancer patients will finally become possible. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.Journal of Cellular Biochemistry 03/2013; 114(3). DOI:10.1002/jcb.24401 · 3.37 Impact Factor
Journal of Cancer Therapy 01/2013; 04(02):678-693. DOI:10.4236/jct.2013.42083
- "Oncogenic mutations in the NRAS gene, a homologue of KRAS, also result in resistance to anti-EGFR agents, but are far less frequent (2% -4% of all cases)  . The RNA expression of amphiregulin (AREG) and epiregulin (EREG), ligands of the EGF receptor, may also be linked with response to cetuximab in KRAS wildtype patients . These findings were recently confirmed in 144 mCRC patients with KRAS wildtype genotype. "