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Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells

BACKGROUND: As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. METHODS: The combined anti...

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Autores principales: Zhang, Mi, Quan, Haitian, Fu, Li, Li, Yun, Fu, Haoyu, Lou, Liguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons Australia, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046080/
https://www.ncbi.nlm.nih.gov/pubmed/33656275
http://dx.doi.org/10.1111/1759-7714.13902
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author Zhang, Mi
Quan, Haitian
Fu, Li
Li, Yun
Fu, Haoyu
Lou, Liguang
author_facet Zhang, Mi
Quan, Haitian
Fu, Li
Li, Yun
Fu, Haoyu
Lou, Liguang
author_sort Zhang, Mi
collection PubMed
description BACKGROUND: As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. METHODS: The combined antitumor effects of HS‐10296, a third‐generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non‐small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. RESULTS: Famitinib strengthened the effects of HS‐10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS‐10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS‐10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS‐10296 and famitinib exerted synergistic antitumor activity in NCI‐H1975 and PC‐9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. CONCLUSIONS: Collectively, our results indicate that HS‐10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third‐generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR‐mutant NSCLC.
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spelling pubmed-80460802021-04-16 Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells Zhang, Mi Quan, Haitian Fu, Li Li, Yun Fu, Haoyu Lou, Liguang Thorac Cancer Original Articles BACKGROUND: As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. METHODS: The combined antitumor effects of HS‐10296, a third‐generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non‐small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. RESULTS: Famitinib strengthened the effects of HS‐10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS‐10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS‐10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS‐10296 and famitinib exerted synergistic antitumor activity in NCI‐H1975 and PC‐9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. CONCLUSIONS: Collectively, our results indicate that HS‐10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third‐generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR‐mutant NSCLC. John Wiley & Sons Australia, Ltd 2021-03-03 2021-04 /pmc/articles/PMC8046080/ /pubmed/33656275 http://dx.doi.org/10.1111/1759-7714.13902 Text en © 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd. 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
Zhang, Mi
Quan, Haitian
Fu, Li
Li, Yun
Fu, Haoyu
Lou, Liguang
Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells
title Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells
title_full Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells
title_fullStr Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells
title_full_unstemmed Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells
title_short Third‐generation EGFR inhibitor HS‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in EGFR‐mutant non‐small cell lung cancer cells
title_sort third‐generation egfr inhibitor hs‐10296 in combination with famitinib, a multi‐targeted tyrosine kinase inhibitor, exerts synergistic antitumor effects through enhanced inhibition of downstream signaling in egfr‐mutant non‐small cell lung cancer cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046080/
https://www.ncbi.nlm.nih.gov/pubmed/33656275
http://dx.doi.org/10.1111/1759-7714.13902
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