Inhibition of the T790M Gatekeeper Mutant of the Epidermal Growth Factor Receptor by EXEL-7647
| Autor: | Christopher Jaeger, A. Douglas Laird, Paul Keast, Dana T. Aftab, Steven Brian Gendreau, Felix Chu, Anushka De Costa, Peiwen Yu, Stephanie Meyer, Yongchang Shi, Frauke Bentzien, Belinda Cancilla, Wentao Zhang, Jean-Francois Martini, Richard Ventura, Lisa Jackman, Jeffery Lutman, Jason Chen, Alison Joly, Jing Wang, Kelly Engell, F. Michael Yakes |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
medicine.medical_specialty Mice Nude Antineoplastic Agents Apoptosis Mice SCID Biology Erlotinib Hydrochloride Mice T790M Gefitinib Cell Line Tumor Internal medicine In Situ Nick-End Labeling medicine Animals Humans ERBB3 Epidermal growth factor receptor Phosphorylation Protein Kinase Inhibitors Cell Proliferation Insulin-like growth factor 1 receptor EGFR inhibitors Dose-Response Relationship Drug Immunohistochemistry Xenograft Model Antitumor Assays respiratory tract diseases ErbB Receptors Endocrinology Oncology Drug Resistance Neoplasm Mutation Quinazolines Cancer research biology.protein Cyclin-dependent kinase 8 Female Azabicyclo Compounds Tyrosine kinase medicine.drug |
| Zdroj: | Clinical Cancer Research. 13:3713-3723 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non–small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.Experimental Design: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies. |
| Databáze: | OpenAIRE |
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