Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction

Osimertinib, a third‐generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), provides marked clinical benefit for patients with EGFR‐activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two ‘...

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Autores principales: Han, Rui, Hao, Shuai, Lu, Conghua, Zhang, Chong, Lin, Caiyu, Li, Li, Wang, Yubo, Hu, Chen, He, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266273/
https://www.ncbi.nlm.nih.gov/pubmed/32239624
http://dx.doi.org/10.1002/1878-0261.12682
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author Han, Rui
Hao, Shuai
Lu, Conghua
Zhang, Chong
Lin, Caiyu
Li, Li
Wang, Yubo
Hu, Chen
He, Yong
author_facet Han, Rui
Hao, Shuai
Lu, Conghua
Zhang, Chong
Lin, Caiyu
Li, Li
Wang, Yubo
Hu, Chen
He, Yong
author_sort Han, Rui
collection PubMed
description Osimertinib, a third‐generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), provides marked clinical benefit for patients with EGFR‐activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two ‘special’ patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib‐resistant non‐small‐cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib‐resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib‐resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC‐9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression‐free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib‐resistant lung cancer cells through promoting Bim‐dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC.
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spelling pubmed-72662732020-06-03 Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction Han, Rui Hao, Shuai Lu, Conghua Zhang, Chong Lin, Caiyu Li, Li Wang, Yubo Hu, Chen He, Yong Mol Oncol Research Articles Osimertinib, a third‐generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), provides marked clinical benefit for patients with EGFR‐activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two ‘special’ patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib‐resistant non‐small‐cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib‐resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib‐resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC‐9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression‐free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib‐resistant lung cancer cells through promoting Bim‐dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC. John Wiley and Sons Inc. 2020-05-05 2020-06 /pmc/articles/PMC7266273/ /pubmed/32239624 http://dx.doi.org/10.1002/1878-0261.12682 Text en © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Han, Rui
Hao, Shuai
Lu, Conghua
Zhang, Chong
Lin, Caiyu
Li, Li
Wang, Yubo
Hu, Chen
He, Yong
Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction
title Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction
title_full Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction
title_fullStr Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction
title_full_unstemmed Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction
title_short Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction
title_sort aspirin sensitizes osimertinib‐resistant nsclc cells in vitro and in vivo via bim‐dependent apoptosis induction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266273/
https://www.ncbi.nlm.nih.gov/pubmed/32239624
http://dx.doi.org/10.1002/1878-0261.12682
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