title: Activation of EGFR Bypass Signaling by TGFα Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells.
abstract: Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling.
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. 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: 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: Aoi
authors.initials: A
authors.lastname: Kuroda
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: 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.
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: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014178:Translocation, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D002227:Carbazoles; D010880:Piperidines; D016211:Transforming Growth Factor alpha; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib