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 ‘...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-06-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.12682 |
| _version_ | 1828123766927917056 |
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| author | Rui Han Shuai Hao Conghua Lu Chong Zhang Caiyu Lin Li Li Yubo Wang Chen Hu Yong He |
| author_facet | Rui Han Shuai Hao Conghua Lu Chong Zhang Caiyu Lin Li Li Yubo Wang Chen Hu Yong He |
| author_sort | Rui Han |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T14:56:55Z |
| format | Article |
| id | doaj.art-306df442d3814158aac9771a111cee34 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-04-11T14:56:55Z |
| publishDate | 2020-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-306df442d3814158aac9771a111cee342022-12-22T04:17:09ZengWileyMolecular Oncology1574-78911878-02612020-06-011461152116910.1002/1878-0261.12682Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis inductionRui Han0Shuai Hao1Conghua Lu2Chong Zhang3Caiyu Lin4Li Li5Yubo Wang6Chen Hu7Yong He8Department of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Ultrasound The First Affiliated Hospital of Chongqing Medical University ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing ChinaOsimertinib, 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.https://doi.org/10.1002/1878-0261.12682apoptosisaspirinEGFR‐TKIosimertinibresistance |
| spellingShingle | Rui Han Shuai Hao Conghua Lu Chong Zhang Caiyu Lin Li Li Yubo Wang Chen Hu Yong He Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction Molecular Oncology apoptosis aspirin EGFR‐TKI osimertinib resistance |
| 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 | apoptosis aspirin EGFR‐TKI osimertinib resistance |
| url | https://doi.org/10.1002/1878-0261.12682 |
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