Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.

Cancer Res 2010 Feb 26;70(3):868-74. Epub 2010 Jan 26.

Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society, Center of Integrated Oncology and Department I of Internal Medicine, University of Köln, Cologne, Germany.

Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFR(T790M) resistance mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFR(T790M) gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR.

Download full-text PDF

Source
http://cancerres.aacrjournals.org/content/early/2010/01/26/0
Web Search
http://cancerres.aacrjournals.org/cgi/doi/10.1158/0008-5472.
Publisher Site
http://dx.doi.org/10.1158/0008-5472.CAN-09-3106DOI Listing
February 2010
49 Reads

Publication Analysis

Top Keywords

egfr inhibitors
20
resistance mutation
12
egfr
8
second-generation egfr
8
inhibitors egfrt790m
8
tumor cells
8
irreversible egfr
8
chemogenomic profiling
8
inhibitors
7
cell lines
4
inhibition linked
4
lines growth-inhibitory
4
egfr-dependent cell
4
linked decreased
4
nsclc egfr-dependent
4
growth-inhibitory potency
4
potency irreversible
4
limited reduced
4
egfrt790m resistance
4
reduced target
4

Altmetric Statistics

Similar Publications