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Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3‐mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against AL...

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Autores principales: Ando, Chihiro, Ichihara, Eiki, Nishi, Tatsuya, Morita, Ayako, Hara, Naofumi, Takada, Kenji, Nakasuka, Takamasa, Watanabe, Hiromi, Kano, Hirohisa, Nishii, Kazuya, Makimoto, Go, Kondo, Takumi, Ninomiya, Kiichiro, Fujii, Masanori, Kubo, Toshio, Ohashi, Kadoaki, Matsuoka, Ken‐ichi, Hotta, Katsuyuki, Tabata, Masahiro, Maeda, Yoshinobu, Kiura, Katsuyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637052/
https://www.ncbi.nlm.nih.gov/pubmed/37715310
http://dx.doi.org/10.1111/cas.15958
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author Ando, Chihiro
Ichihara, Eiki
Nishi, Tatsuya
Morita, Ayako
Hara, Naofumi
Takada, Kenji
Nakasuka, Takamasa
Watanabe, Hiromi
Kano, Hirohisa
Nishii, Kazuya
Makimoto, Go
Kondo, Takumi
Ninomiya, Kiichiro
Fujii, Masanori
Kubo, Toshio
Ohashi, Kadoaki
Matsuoka, Ken‐ichi
Hotta, Katsuyuki
Tabata, Masahiro
Maeda, Yoshinobu
Kiura, Katsuyuki
author_facet Ando, Chihiro
Ichihara, Eiki
Nishi, Tatsuya
Morita, Ayako
Hara, Naofumi
Takada, Kenji
Nakasuka, Takamasa
Watanabe, Hiromi
Kano, Hirohisa
Nishii, Kazuya
Makimoto, Go
Kondo, Takumi
Ninomiya, Kiichiro
Fujii, Masanori
Kubo, Toshio
Ohashi, Kadoaki
Matsuoka, Ken‐ichi
Hotta, Katsuyuki
Tabata, Masahiro
Maeda, Yoshinobu
Kiura, Katsuyuki
author_sort Ando, Chihiro
collection PubMed
description Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3‐mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK‐rearranged non‐small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK‐rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK‐rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal–epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib‐treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK‐rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin‐15 (IL‐15) mRNA levels were elevated in gilteritinib‐treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL‐15 production along with NK cell infiltration may constitute components of the gilteritinib‐mediated antitumor responses in ALK‐rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK‐rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.
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spelling pubmed-106370522023-11-15 Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer Ando, Chihiro Ichihara, Eiki Nishi, Tatsuya Morita, Ayako Hara, Naofumi Takada, Kenji Nakasuka, Takamasa Watanabe, Hiromi Kano, Hirohisa Nishii, Kazuya Makimoto, Go Kondo, Takumi Ninomiya, Kiichiro Fujii, Masanori Kubo, Toshio Ohashi, Kadoaki Matsuoka, Ken‐ichi Hotta, Katsuyuki Tabata, Masahiro Maeda, Yoshinobu Kiura, Katsuyuki Cancer Sci ORIGINAL ARTICLES Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3‐mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK‐rearranged non‐small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK‐rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK‐rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal–epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib‐treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK‐rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin‐15 (IL‐15) mRNA levels were elevated in gilteritinib‐treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL‐15 production along with NK cell infiltration may constitute components of the gilteritinib‐mediated antitumor responses in ALK‐rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK‐rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings. John Wiley and Sons Inc. 2023-09-15 /pmc/articles/PMC10637052/ /pubmed/37715310 http://dx.doi.org/10.1111/cas.15958 Text en © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle ORIGINAL ARTICLES
Ando, Chihiro
Ichihara, Eiki
Nishi, Tatsuya
Morita, Ayako
Hara, Naofumi
Takada, Kenji
Nakasuka, Takamasa
Watanabe, Hiromi
Kano, Hirohisa
Nishii, Kazuya
Makimoto, Go
Kondo, Takumi
Ninomiya, Kiichiro
Fujii, Masanori
Kubo, Toshio
Ohashi, Kadoaki
Matsuoka, Ken‐ichi
Hotta, Katsuyuki
Tabata, Masahiro
Maeda, Yoshinobu
Kiura, Katsuyuki
Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer
title Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer
title_full Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer
title_fullStr Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer
title_full_unstemmed Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer
title_short Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer
title_sort efficacy of gilteritinib in comparison with alectinib for the treatment of alk‐rearranged non‐small cell lung cancer
topic ORIGINAL ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637052/
https://www.ncbi.nlm.nih.gov/pubmed/37715310
http://dx.doi.org/10.1111/cas.15958
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