title: Overcoming EGFR Bypass Signal-Induced Acquired Resistance to ALK Tyrosine Kinase Inhibitors in ALK-Translocated Lung Cancer.
abstract: Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination treatment partially restored the sensitivity to ceritinib.
  
  
  
  This study proposes a preclinical rationale to use ALK-TKIs and afatinib combination therapy for ALK-translocated lung cancers that have acquired resistance to ALK-TKIs through EGFR pathway activation. Mol Cancer Res; 15(1); 106-14. ©2016 AACR.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Miyawaki
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan. hiroyukiyasuda@a8.keio.jp ksoejima@cpnet.med.keio.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Tani
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Hamamoto
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Arai
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ishioka
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohgino
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Shigenari
authors.initials: S
authors.lastname: Nukaga
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawada
authors.affiliation: Keio Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naoki
authors.affiliation: Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan. hiroyukiyasuda@a8.keio.jp ksoejima@cpnet.med.keio.ac.jp.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Soejima
mesh_terms: D000077716:Afatinib; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones; D014178:Translocation, Genetic
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013450:Sulfones; D000077716:Afatinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib