Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients
Abstract Background Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2‐positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib. Methods Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of p...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.148 |
| _version_ | 1818825280909737984 |
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| author | Zuhua Chen Yingying Xu Jifang Gong Furong Kou Mengqi Zhang Tiantian Tian Xiaotian Zhang Cheng Zhang Jian Li Zhongwu Li Yumei Lai Jianjun Zou Xiaoyu Zhu Jing Gao Lin Shen |
| author_facet | Zuhua Chen Yingying Xu Jifang Gong Furong Kou Mengqi Zhang Tiantian Tian Xiaotian Zhang Cheng Zhang Jian Li Zhongwu Li Yumei Lai Jianjun Zou Xiaoyu Zhu Jing Gao Lin Shen |
| author_sort | Zuhua Chen |
| collection | DOAJ |
| description | Abstract Background Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2‐positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib. Methods Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of pyrotinib. A pyrotinib‐combined strategy was proposed, which was validated in preclinical AVATAR mouse and in clinical patients enrolled in a phase I clinical trial (NCT03480256). Results Dysregulation of CCND1‐CDK4/6‐Rb axis might be the key to pyrotinib refractory. The strategy of pyrotinib combined with a CDK4/6 inhibitor SHR6390 was proposed and validated in preclinical AVATAR mouse, which was successfully verified in clinical patients. For five patients treated with pyrotinib plus SHR6390 who had available response evaluation, the best response was partial response in three patients, stable disease in one patient, and progressive disease in one patient. The progression‐free survival times were 120, 200, 532, 109, and 57 days, respectively. Conclusions This translational study suggests that pyrotinib combined with SHR6390 may serve as a promising strategy for patients with HER2‐positive GC. Trial registration The ClinicalTrials.gov identifiers are NCT02378389 (https://clinicaltrials.gov/ct2/show/study/NCT02378389, registered in 11 February 2015) and NCT03480256 (https://clinicaltrials.gov/ct2/show/study/NCT03480256, registered in 8 March 2018). |
| first_indexed | 2024-12-19T00:09:16Z |
| format | Article |
| id | doaj.art-9289f0ef0b4e469989fe0410bb6ac7af |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-12-19T00:09:16Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-9289f0ef0b4e469989fe0410bb6ac7af2022-12-21T20:46:04ZengWileyClinical and Translational Medicine2001-13262020-08-01104n/an/a10.1002/ctm2.148Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patientsZuhua Chen0Yingying Xu1Jifang Gong2Furong Kou3Mengqi Zhang4Tiantian Tian5Xiaotian Zhang6Cheng Zhang7Jian Li8Zhongwu Li9Yumei Lai10Jianjun Zou11Xiaoyu Zhu12Jing Gao13Lin Shen14Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology Peking University Cancer Hospital and Institute Beijing ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology Peking University Cancer Hospital and Institute Beijing ChinaJiangsu Hengrui Medicine Co, Ltd Jiangsu ChinaJiangsu Hengrui Medicine Co, Ltd Jiangsu ChinaNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Shenzhen ChinaKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology Peking University Cancer Hospital and Institute Beijing ChinaAbstract Background Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2‐positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib. Methods Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of pyrotinib. A pyrotinib‐combined strategy was proposed, which was validated in preclinical AVATAR mouse and in clinical patients enrolled in a phase I clinical trial (NCT03480256). Results Dysregulation of CCND1‐CDK4/6‐Rb axis might be the key to pyrotinib refractory. The strategy of pyrotinib combined with a CDK4/6 inhibitor SHR6390 was proposed and validated in preclinical AVATAR mouse, which was successfully verified in clinical patients. For five patients treated with pyrotinib plus SHR6390 who had available response evaluation, the best response was partial response in three patients, stable disease in one patient, and progressive disease in one patient. The progression‐free survival times were 120, 200, 532, 109, and 57 days, respectively. Conclusions This translational study suggests that pyrotinib combined with SHR6390 may serve as a promising strategy for patients with HER2‐positive GC. Trial registration The ClinicalTrials.gov identifiers are NCT02378389 (https://clinicaltrials.gov/ct2/show/study/NCT02378389, registered in 11 February 2015) and NCT03480256 (https://clinicaltrials.gov/ct2/show/study/NCT03480256, registered in 8 March 2018).https://doi.org/10.1002/ctm2.148CDK inhibitorpyrotinibrefractory mechanisms |
| spellingShingle | Zuhua Chen Yingying Xu Jifang Gong Furong Kou Mengqi Zhang Tiantian Tian Xiaotian Zhang Cheng Zhang Jian Li Zhongwu Li Yumei Lai Jianjun Zou Xiaoyu Zhu Jing Gao Lin Shen Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients Clinical and Translational Medicine CDK inhibitor pyrotinib refractory mechanisms |
| title | Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients |
| title_full | Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients |
| title_fullStr | Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients |
| title_full_unstemmed | Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients |
| title_short | Pyrotinib combined with CDK4/6 inhibitor in HER2‐positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients |
| title_sort | pyrotinib combined with cdk4 6 inhibitor in her2 positive metastatic gastric cancer a promising strategy from avatar mouse to patients |
| topic | CDK inhibitor pyrotinib refractory mechanisms |
| url | https://doi.org/10.1002/ctm2.148 |
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