1. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.
- Author
-
Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Klüter S, Pawar VG, Reuter C, Heuckmann JM, Weiss J, Ruddigkeit L, Rabiller M, Koker M, Simard JR, Getlik M, Yuza Y, Chen TH, Greulich H, Thomas RK, and Rauh D
- Subjects
- Afatinib, Amino Acid Substitution, Animals, Apoptosis drug effects, Blotting, Western, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Cluster Analysis, ErbB Receptors metabolism, Furans pharmacology, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology, Molecular Structure, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors classification, Pyridines pharmacology, Pyrimidines pharmacology, Quinazolines pharmacology, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Signal Transduction drug effects, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Mutation, Protein Kinase Inhibitors pharmacology
- Abstract
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.
- Published
- 2010
- Full Text
- View/download PDF