title: EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer.
abstract: ALK gene fusion occurs in approximately 3-7% of non-small cell lung cancer (NSCLC). For patients with ALK positive NCSLC, crizotinib and ceritinib are FDA approved ALK inhibitors, however, patients inevitably acquire resistance to such therapies typically within one to two years. Interrogation of in vitro ALK-positive NSCLC cell line models of acquired resistance to first and second-generation ALK inhibitors revealed acquired epithelial-to-mesenchymal transition (EMT) mechanisms. Here we demonstrated that knockdown of upregulated mesenchymal markers in acquired resistant lines decreased the invasive and migratory capabilities of the cells, however, it did not restore sensitivity to ALK inhibitors. Removing drug for 5 weeks from H3122 cell line that acquired resistance to ceritinib restored its sensitivity to ceritinib. In addition, HSP90 inhibitors ganetespib and 17-AAG were potent in inducing cell death in cell lines resistant to crizotinib and ceritinib. Taken together, EMT does not drive resistance to ALK inhibitors and HSP90 inhibition demonstrates more efficacy when further ALK inhibition may not. This study warrants more exploration of HSP90 inhibitors for ALK-positive patients who progress on 1st and 2nd line ALK inhibitor therapy.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA.
authors.forename: Arjan
authors.initials: A
authors.lastname: Gower
authors.affiliation: Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA.
authors.forename: Wei-Hsun
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA.
authors.forename: Shuo-Tse
authors.initials: ST
authors.lastname: Hsu
authors.affiliation: Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA. Electronic address: gg496@georgetown.edu.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; C522504:EML4-ALK fusion protein, human; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion
keywords: ALK-positive NSCLC; Ceritinib; Epithelial–mesenchymal transition; HSP90 inhibition; Resistance