title: Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation.
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.
authors.affiliation: 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.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Haridas B
authors.initials: HB
authors.lastname: Rode
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heynck
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Florian
authors.initials: F
authors.lastname: Fischer
authors.forename: Sabine
authors.initials: S
authors.lastname: Klüter
authors.forename: Vijaykumar G
authors.initials: VG
authors.lastname: Pawar
authors.forename: Cecile
authors.initials: C
authors.lastname: Reuter
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weiss
authors.forename: Lars
authors.initials: L
authors.lastname: Ruddigkeit
authors.forename: Matthias
authors.initials: M
authors.lastname: Rabiller
authors.forename: Mirjam
authors.initials: M
authors.lastname: Koker
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yuza
authors.forename: Tzu-Hsiu
authors.initials: TH
authors.lastname: Chen
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000077716:Afatinib; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000077716:Afatinib; D066246:ErbB Receptors; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C509204:PD168393; C522973:PI103