Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context
Summary: Background: The PHILA study suggests that pyrotinib, trastuzumab, and docetaxel significantly improved progression-free survival (PFS) compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2-positive metastatic breast cancer. In this study, we aimed to investigate...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-11-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424004158 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846168271627223040 |
|---|---|
| author | Shuning Liu Bo Lan Yuanyi Wang Tao Yang Lixi Li Hewei Ge Cheng Zeng Binghe Xu Haili Qian Fei Ma |
| author_facet | Shuning Liu Bo Lan Yuanyi Wang Tao Yang Lixi Li Hewei Ge Cheng Zeng Binghe Xu Haili Qian Fei Ma |
| author_sort | Shuning Liu |
| collection | DOAJ |
| description | Summary: Background: The PHILA study suggests that pyrotinib, trastuzumab, and docetaxel significantly improved progression-free survival (PFS) compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2-positive metastatic breast cancer. In this study, we aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and provide further insights for the PHILA trial. Methods: The in vitro activity of combination treatments was assessed through cell biological and biochemical experiments. The in vivo efficacy was evaluated in cell-derived xenografts, a TUBO tumour model, and one clinical case. Next-generation sequencing was performed on circulating tumour DNA (ctDNA) from patients in the PHILA trial. Findings: The combination of pyrotinib and trastuzumab more effectively inhibited cell growth than pyrotinib or trastuzumab alone in models of HER2-dependent breast cancer. It potentiated membrane HER2 ubiquitination and downregulation, which resulted in a comprehensive blockade of the HER2 signalling pathway. The pyrotinib-altered membrane HER2 levels had no significant effect on trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). We further validated the synergistic mechanisms in TUBO tumours and one clinical case, rather than models of HCC1954 cells harbouring the PIK3CA H1047R mutation. Similarly, in our centre cohort of the PHILA study, patients with genetic alterations in the HER2 signalling cascade had significantly shorter median PFS than individuals with the wild-type pathway. Interpretation: Our findings underscore the robust synergy between pyrotinib and trastuzumab in overcoming HER2 dependency and provide a rationale for pyrotinib, trastuzumab, and docetaxel as one of the optimal choices for patients with untreated HER2-positive metastatic breast cancer, who are dependent on the HER2 signalling cascade. Funding: This work was supported by the National Key Research and Development Program of China (2021YFF1201300), the National Natural Science Foundation of China (82172875), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-001), and the Joint Innovative Fund of Beijing Natural Science Foundation and Changping District (L234004). |
| format | Article |
| id | doaj-art-9bb421ef3cf74b95b5cb31e0773cfbb1 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-9bb421ef3cf74b95b5cb31e0773cfbb12024-11-14T04:32:18ZengElsevierEBioMedicine2352-39642024-11-01109105379Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in contextShuning Liu0Bo Lan1Yuanyi Wang2Tao Yang3Lixi Li4Hewei Ge5Cheng Zeng6Binghe Xu7Haili Qian8Fei Ma9Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDepartment of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Corresponding author. Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Corresponding author.Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Corresponding author. Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.Summary: Background: The PHILA study suggests that pyrotinib, trastuzumab, and docetaxel significantly improved progression-free survival (PFS) compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2-positive metastatic breast cancer. In this study, we aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and provide further insights for the PHILA trial. Methods: The in vitro activity of combination treatments was assessed through cell biological and biochemical experiments. The in vivo efficacy was evaluated in cell-derived xenografts, a TUBO tumour model, and one clinical case. Next-generation sequencing was performed on circulating tumour DNA (ctDNA) from patients in the PHILA trial. Findings: The combination of pyrotinib and trastuzumab more effectively inhibited cell growth than pyrotinib or trastuzumab alone in models of HER2-dependent breast cancer. It potentiated membrane HER2 ubiquitination and downregulation, which resulted in a comprehensive blockade of the HER2 signalling pathway. The pyrotinib-altered membrane HER2 levels had no significant effect on trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). We further validated the synergistic mechanisms in TUBO tumours and one clinical case, rather than models of HCC1954 cells harbouring the PIK3CA H1047R mutation. Similarly, in our centre cohort of the PHILA study, patients with genetic alterations in the HER2 signalling cascade had significantly shorter median PFS than individuals with the wild-type pathway. Interpretation: Our findings underscore the robust synergy between pyrotinib and trastuzumab in overcoming HER2 dependency and provide a rationale for pyrotinib, trastuzumab, and docetaxel as one of the optimal choices for patients with untreated HER2-positive metastatic breast cancer, who are dependent on the HER2 signalling cascade. Funding: This work was supported by the National Key Research and Development Program of China (2021YFF1201300), the National Natural Science Foundation of China (82172875), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-001), and the Joint Innovative Fund of Beijing Natural Science Foundation and Changping District (L234004).http://www.sciencedirect.com/science/article/pii/S2352396424004158PHILA studyPyrotinibTrastuzumabHER2-positive breast cancer |
| spellingShingle | Shuning Liu Bo Lan Yuanyi Wang Tao Yang Lixi Li Hewei Ge Cheng Zeng Binghe Xu Haili Qian Fei Ma Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context EBioMedicine PHILA study Pyrotinib Trastuzumab HER2-positive breast cancer |
| title | Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context |
| title_full | Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context |
| title_fullStr | Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context |
| title_full_unstemmed | Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context |
| title_short | Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trialResearch in context |
| title_sort | pyrotinib and trastuzumab combination treatment synergistically overcomes her2 dependency in her2 positive breast cancer insights from the phila trialresearch in context |
| topic | PHILA study Pyrotinib Trastuzumab HER2-positive breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424004158 |
| work_keys_str_mv | AT shuningliu pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT bolan pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT yuanyiwang pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT taoyang pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT lixili pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT heweige pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT chengzeng pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT binghexu pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT hailiqian pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext AT feima pyrotinibandtrastuzumabcombinationtreatmentsynergisticallyovercomesher2dependencyinher2positivebreastcancerinsightsfromthephilatrialresearchincontext |