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• W2341423411 abstract "ABSTRACT Aim: Alectinib (CH/RO5424802) is a second generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI). It has been reported to overcome acquired resistance to the first generation ALK-TKI, crizotinib, in a preclinical study (Cancer Cell 19, 2011: 679-90). A phase I/II clinical trial of alectinib for ALK positive non-small cell lung cancer (NSCLC) showed an unprecedented response rate (93.5 % in phase II portion) and the drug seemed to lead to less toxicities than crizotinib (Lancet Oncol 14, 2013: 590-98). However, subsequent resistance to alectinib is expected after its approval. Thus, we need to consider the therapeutic strategy to overcome the resistance to alectinib in advance. Methods: Two alectinib-resistant H2228/CHR and ABC-11/CHR NSCLC cell lines from H2228 and ABC-11, respectively, harboring EML4-ALK fusion genes were established by continuous exposure to alectinib. We characterized the resistant cell lines using MTT assay, western blotting, immunohistochemistry, polymerase chain reaction, fluorescent in situ hybridization, phospho-receptor tyrosine kinase array, comparative genomic hybridization, RNA array, ELISA and xenograft models. Results: H2228/CHR and ABC-11/CHR cells showed 130-fold and 17-fold higher resistance to alectinib than their respective parent cells in vitro. H2228/CHR cells had lost EML4-ALK fusion gene and ALK protein expression. In addition, the resistant cells overexpressed IGF1R, and were sensitive to IGF1R-TKI (TAE684) as a result. While ABC-11/CHR cells reduced phospho-ALK in spite of preservation of total ALK protein, they activated MET with increment of its ligand (hepatocyte growth factor) as an autocrine action. Because crizotinib originally functions as MET-TKI along with ALK-TKI, ABC-11/CHR was sensitive to the drug both in vitro and in vivo. Conclusions: Loss or inactivation of ALK leads to the acquired resistance to alectinib in the two cell lines we established. In addition, signaling switch from ALK to IGF1R or MET was observed. IGF1R inhibitor or MET inhibitor was effective on such cases. Thus, ALK positive NSCLC patients refractory to alectinib might benefit from IGF1R or MET inhibitors. Disclosure: K. Hotta: Honoraria from speaker's bureau from Chugai pharmaceutical CO., LTD.; N. Takigawa: Honoraria from speaker's bureau from Pfizer Inc. Japan; K. Kiura: Honoraria from speaker's bureau from Chugai pharmaceutical CO., LTD., Pfizer Inc. Japan and Novartis Pharma K.K. All other authors have declared no conflicts of interest." @default.
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• W2341423411 date "2014-09-01" @default.
• W2341423411 modified "2023-09-27" @default.
• W2341423411 title "Acquired Resistance to a New Alk Inhibitor, Alectinib in Lung Cancer" @default.
• W2341423411 doi "https://doi.org/10.1093/annonc/mdu358.15" @default.
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