title: EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.
abstract: Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Amato
authors.affiliation: Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Hastings
authors.affiliation: Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Meador
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, Tennessee.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Colvin
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee. jin.chen@vanderbilt.edu.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C000605793:ALW-II-41-27; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D036104:Receptor, EphA2