title: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.
abstract: Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.
authors.affiliation: Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.forename: Nadia
authors.initials: N
authors.lastname: Godin-Heymann
authors.forename: Ross A
authors.initials: RA
authors.lastname: Okimoto
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Harris
authors.forename: David R
authors.initials: DR
authors.lastname: Driscoll
authors.forename: Panos
authors.initials: P
authors.lastname: Fidias
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: John P
authors.initials: JP
authors.lastname: McGinnis
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
authors.forename: Sreenath V
authors.initials: SV
authors.lastname: Sharma
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Isselbacher
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000634:Aminoquinolines; D000814:Aniline Compounds; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000634:Aminoquinolines; D000814:Aniline Compounds; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D009930:Organic Chemicals; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib; C413879:EKB 569