1. Introduction The importance of EFGR in driving tumor genesis in NSCLC, as well as other types of cancer, has been clinically validated and inhibitors of EGFR have been approved for treatment of a series of cancer. ATP competitive inhibitors of the TKD domain include gefitinib (Iressa®).1 However, mutations in the tyrosine kinase domain have been shown to be strongly associated with the response of NSCLC patients to gefitinib treatment. To improve the understanding of the acquired resistance mechanism, molecular modeling is a good tool for this purpose. Accurate computation of free energies of binding remains a key challenge for computer-aided drug design.2-3 2. Results and Discussion In this work, we performed simulations of three different point mutation of EGFR in complex with gefitinib: L858R, T790M and R831H. The first two mutations are the most frequent in patients with NSCLC; L858R was found to be a responsive mutation and T790M a resistance mutation, confirming experimental data. The results of R831H (Fig.1), a less common and recently discovered mutation, show a good responsive behaviour but less than L858R. The agreement of our results with clinical data proves the reliability of molecular simulations to predict the behavior of this kind of complex.

Molecular modeling investigation of EGFR mutations and their response to Iressa

SANTESE, FRANCESCA;LAURINI, ERIK;PRICL, SABRINA;
2011

Abstract

1. Introduction The importance of EFGR in driving tumor genesis in NSCLC, as well as other types of cancer, has been clinically validated and inhibitors of EGFR have been approved for treatment of a series of cancer. ATP competitive inhibitors of the TKD domain include gefitinib (Iressa®).1 However, mutations in the tyrosine kinase domain have been shown to be strongly associated with the response of NSCLC patients to gefitinib treatment. To improve the understanding of the acquired resistance mechanism, molecular modeling is a good tool for this purpose. Accurate computation of free energies of binding remains a key challenge for computer-aided drug design.2-3 2. Results and Discussion In this work, we performed simulations of three different point mutation of EGFR in complex with gefitinib: L858R, T790M and R831H. The first two mutations are the most frequent in patients with NSCLC; L858R was found to be a responsive mutation and T790M a resistance mutation, confirming experimental data. The results of R831H (Fig.1), a less common and recently discovered mutation, show a good responsive behaviour but less than L858R. The agreement of our results with clinical data proves the reliability of molecular simulations to predict the behavior of this kind of complex.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2838107
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