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Targeted delivery of CD44s-siRNA by ScFv overcomes de novo resistance to cetuximab in triple negative breast cancer
In this study, we show that impaired EGFR degradation is crucial for resistance to cetuximab, which depends on the cell surface molecule CD44. To further investigate the role of CD44 in EGFR signaling and its treatment potential, we developed a targeting fusion protein composed of an anti-EGFR scFv generated from cetuximab and truncated protamine, called Ce-tP. CD44 siRNA can be specifically delivered into EGFR-positive TNBC cells by Ce-tP. Efficient knockdown of CD44 and suppression of both EGFR and downstream signaling by the Ce-tP/siRNA complex were observed in EGFR-positive TNBC cells. More importantly, our results als...
Source: Molecular Immunology - May 17, 2018 Category: Allergy & Immunology Source Type: research

MicroRNA-9 enhances sensitivity to cetuximab in epithelial phenotype hepatocellular carcinoma cells through regulation of the eukaryotic translation initiation factor 5A-2.
Authors: Xue F, Liang Y, Li Z, Liu Y, Zhang H, Wen Y, Yan L, Tang Q, Xiao E, Zhang D Abstract Hepatocellular carcinoma (HCC) is one of the most widespread malignant human tumors worldwide. Treatment options include radiotherapy, surgical intervention and chemotherapy; however, drug resistance is an ongoing treatment concern. In the present study, the effects of a microRNA (miR/miRNA), miR-9, on the sensitivity of HCC cell lines to the epidermal growth factor receptor inhibitor, cetuximab, were examined. miR-9 has been proposed to serve a role in tumorigenesis and tumor progression. In the present study, bioinformat...
Source: Oncology Letters - February 7, 2018 Category: Cancer & Oncology Tags: Oncol Lett Source Type: research

The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics
Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that influence the response to cisplatin in HNS...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Martens-de Kemp, S. R., Brink, A., van der Meulen, I. H., de Menezes, R. X., te Beest, D. E., Leemans, C. R., van Beusechem, V. W., Braakhuis, B. J. M., Brakenhoff, R. H. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer.
Authors: Geißler AL, Geißler M, Kottmann D, Lutz L, Fichter CD, Fritsch R, Weddeling B, Makowiec F, Werner M, Lassmann S Abstract EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as w...
Source: Oncotarget - February 17, 2017 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

eIF5A2 is an alternative pathway for cell proliferation in cetuximab-treated epithelial hepatocellular carcinoma.
This study aimed to evaluate the role of eIF5A2 in cetuximab-treated HCC cell proliferation, and whether eIF5A2 specific inhibitor GC7 has any effects on cetuximab-mediated proliferation inhibition in HCC cell lines. It was observed that GC7 significantly inhibited cell proliferation in HCC cell lines. GC7 synergized cetuximab to inhibit the proliferation in epithelial HCC cell lines HepG2, Huh7 and Hep3B, but not in mesenchymal cell lines SNU387 and SNU449. Knockdown of eIF5A-2 by specific siRNA exhibited the similar effects as GC7 did. In cetuximab-treated cells, cetuximab decreased the protein level of EGFR and phosphor...
Source: American Journal of Translational Research - December 3, 2016 Category: Research Tags: Am J Transl Res Source Type: research

EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells.
CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients. PMID: 27873490 [PubMed - in process]
Source: Yonsei Medical Journal - November 24, 2016 Category: Universities & Medical Training Authors: Chang H, Sung JH, Moon SU, Kim HS, Kim JW, Lee JS Tags: Yonsei Med J Source Type: research

Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
Conclusions We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.
Source: Gut - July 7, 2016 Category: Gastroenterology Authors: Kloth, M., Ruesseler, V., Engel, C., Koenig, K., Peifer, M., Mariotti, E., Kuenstlinger, H., Florin, A., Rommerscheidt-Fuss, U., Koitzsch, U., Wodtke, C., Ueckeroth, F., Holzapfel, S., Aretz, S., Propping, P., Loeffler, M., Merkelbach-Bruse, S., Odenthal, Tags: Colon cancer Source Type: research

N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of NSCLC cells to cetuximab through inhibition of eukaryotic translation initiation factor 5A2 activation.
CONCLUSIONS: These findings demonstrate that combined treatment with GC7 could enhance cetuximab sensitivity by inhibiting EIF5A2 in NSCLC cells, implying the potential clinical application of GC7 in cetuximab-based chemotherapy for NSCLC patients. PMID: 27097942 [PubMed - in process]
Source: European Review for Medical and Pharmacological Sciences - April 23, 2016 Category: Drugs & Pharmacology Tags: Eur Rev Med Pharmacol Sci Source Type: research

miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells.
Authors: Gomes SE, Simões AE, Pereira DM, Castro RE, Rodrigues CM, Borralho PM Abstract miR-143 and miR-145 are downregulated in colon cancer. Here, we tested the effect of restoring these miRNAs on sensitization to cetuximab in mutant KRAS (HCT116 and SW480) and wild-type KRAS (SW48) colon cancer cells. We evaluated cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and the modulation of signaling pathways involved in immune effector cell-mediated elimination of cancer cells. Stable miR-143 or miR-145 overexpression increased cell sensitivity to cetuximab, resulting in a significant increase of ce...
Source: Oncotarget - January 31, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells.
Authors: Du C, Wang X, Zhang J, Liu X, Zhu J, Liu Y Abstract Paxillin (PXN) encodes a 68-kDa focal adhesion-associated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 nor...
Source: Oncology Reports - November 7, 2015 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

STAT1 and Cisplatin/Cetuximab in HNSCC
Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGF receptor (EGFR) inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at s...
Source: Molecular Cancer Therapeutics - September 2, 2015 Category: Cancer & Oncology Authors: Schmitt, N. C., Trivedi, S., Ferris, R. L. Tags: Cancer Biology and Signal Transduction Source Type: research

Abstract 916: The molecular landscape of colorectal cancer cell lines unveils clinically actionable targets
In conclusion our data suggest that overexpression of TK outliers drives primary resistance to EGFR blockade, and could be used to identify patients unlikely to respond to cetuximab or panitumumab. Moreover, the approach described here can be used to pinpoint colorectal cancers with exquisite dependencies to individual kinases for which clinically approved drugs are already available.Citation Format: Mariangela Russo, Gabriele Picco, Carlotta Cancelliere, Giorgio Corti, Emanuele Valtorta, Silvio Veronese, Marco Beccuti, Francesca Cordero, Federica Di Nicolantonio, Enzo Medico, Alberto Bardelli. The molecular landscape of c...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Russo, M., Picco, G., Cancelliere, C., Corti, G., Valtorta, E., Veronese, S., Beccuti, M., Cordero, F., Di Nicolantonio, F., Medico, E., Bardelli, A. Tags: Prevention Research Source Type: research

Abstract 757: Activation of receptor-interacting serine/threonine protein kinase-2 (RIP2K) via EGFR-mediated CRAF transactivation induces the acquired resistance to Dabrafenib in BRAF V600E mutant non-small cell lung cancer
Discussion: Taken together, these findings suggest that the acquired resistance to Dabrafenib in BRAF V600E mutant NSCLC is uniquely mediated by EGFR-RAS-RIPK2-ERK signaling, bypassing MEK1/2, which may necessitate therapeutic strategies different from those of melanoma.Citation Format: Kangwon Jang, Jinyoung Sohn, Sung-Moo Kim, Kyoung Jin Kim, Byoung Chul Cho. Activation of receptor-interacting serine/threonine protein kinase-2 (RIP2K) via EGFR-mediated CRAF transactivation induces the acquired resistance to Dabrafenib in BRAF V600E mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Jang, K., Sohn, J., Kim, S.-M., Kim, K. J., Cho, B. C. Tags: Experimental and Molecular Therapeutics Source Type: research

Targeting of the EGFR/β1 integrin connecting proteins PINCH1 and Nck2 radiosensitizes three-dimensional SCC cell cultures.
Authors: Rossow L, Eke I, Dickreuter E, Cordes N Abstract Epidermal growth factor receptor (EGFR) signaling plays an important role in tumor cell resistance to therapy. In addition to ligand binding, mutual and cooperative interactions of EGFR with integrin cell adhesion receptors critically influence proper downstream signaling through a number of bridging adapter proteins. In the present study, we analyzed the role of two of these adapter proteins, called PINCH1 and Nck2, for cellular radioresistance in combination with EGFR-targeting using the monoclonal antibody cetuximab. siRNA-mediated knockdown of PINCH1 or ...
Source: Oncology Reports - May 28, 2015 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer.
Abstract Breast cancers bear overexpression of neurokinin-1 (NK-1). The aim of this study was to investigate the relationship between NK-1 and EGFR in triple negative breast cancers (TNBCs). Immunohistochemistry was performed to investigate NK-1 and EGFR expressions in TNBCs. [Sar(9),Met(O2)(11)] substance P (SMSP) was used to activate NK-1 in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. L-733060 and siRNA against NK-1 was used to inhibit NK-1. The in vitro regulatory effect of NK-1 was determined using CCK-8 proliferation assay. The effects of NK-1 activation and inhibition on EGFR and its downstreaming pathwa...
Source: Cellular Signalling - March 25, 2015 Category: Cytology Authors: Wang JG, Juan Y, Hu JL, Yang WL, Ren H, Ding D, Zhang L, Liu XP Tags: Cell Signal Source Type: research

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