title: Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases.
abstract: Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.
authors.affiliation: Department of Clinical Pharmaceutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan.
authors.forename: Hideko
authors.initials: H
authors.lastname: Isozaki
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan. Department of Hematology/Oncology Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. kkiura@md.okayama-u.ac.jp ichiha-e@md.okayama-u.ac.jp.
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Medical School, Okayama City, Okayama, Japan.
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.affiliation: Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama City, Okayama, Japan.
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Medical School, Okayama City, Okayama, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ochi
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yasugi
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ninomiya
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Medical School, Okayama City, Okayama, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yamane
authors.affiliation: Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama City, Okayama, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa City, Ishikawa, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama City, Okayama, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hosokawa
authors.affiliation: Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama City, Okayama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Bessho
authors.affiliation: Department of Clinical Pharmaceutics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan.
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.affiliation: Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama City, Okayama, Japan. kkiura@md.okayama-u.ac.jp ichiha-e@md.okayama-u.ac.jp.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics
chemical_list: C000597236:IGF1R protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D017451:Receptors, Somatomedin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; C581292:ERBB3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1