Journal
MOLECULAR CANCER THERAPEUTICS
Volume 11, Issue 11, Pages 2394-2400Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-12-0644-T
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Funding
- EU FP7 ContraCancrum [ICT-2007.5.30]
- p-medicine [ICT-2009.5.3]
- NIH grant at the Pittsburgh Supercomputing Center (PSC) [NIH RC2GM093307, MCB110017]
- TeraGrid/XSEDE NSF grant [TG-MCB090174]
- EPSRC [EP/I034602/1] Funding Source: UKRI
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The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non-small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without. Mol Cancer Ther; 11(11); 2394-400. (c) 2012 AACR.
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