Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer
Curation statements for this article:-
Curated by eLife
eLife assessment
This study presents a valuable finding that the combined use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy against HER2+/HR+ breast cancer cells. The evidence supporting the claims of the authors is rather solid. The work will be of interest to medical biologists and clinical doctors working on breast cancer.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Cancer Biology (eLife)
Abstract
Recent evidences from clinical trials (NCT04486911) revealed that the combination of pyrotinib, letrozole, and dalpiciclib exerted optimistic therapeutic effect in treating HER2 + HR + breast cancer; however, the underlying molecular mechanism remained elusive. Through the drug sensitivity test, the drug combination efficacy of pyrotinib, tamoxifen, and dalpiciclib to BT474 cells was tested. The underlying molecular mechanisms were investigated using immunofluorescence, Western blot analysis, immunohistochemical staining, and cell cycle analysis. Potential risk factor that may indicate the responsiveness to drug treatment in HER2 + /HR + breast cancer was identified using RNA-sequence and evaluated using immunohistochemical staining and in vivo drug susceptibility test. We found that pyrotinib combined with dalpiciclib exerted better cytotoxic efficacy than pyrotinib combined with tamoxifen in BT474 cells. Degradation of HER2 could enhance ER nuclear transportation, activating ER signaling pathway in BT474 cells, whereas dalpiciclib could partially abrogate this process. This may be the underlying mechanism by which combination of pyrotinib, tamoxifen, and dalpiciclib exerted best cytotoxic effect. Furthermore, CALML5 was revealed to be a risk factor in the treatment of HER2 + /HR + breast cancer and the usage of dalpiciclib might overcome the drug resistance to pyrotinib + tamoxifen due to CALML5 expression. Our study provided evidence that the usage of dalpiciclib in the treatment of HER2 + /HR + breast cancer could partially abrogate the estrogen signaling pathway activation caused by anti-HER2 therapy and revealed that CALML5 could serve as a risk factor in the treatment of HER2 + /HR + breast cancer.
Article activity feed
-
-
Author Response
Reviewer #1 (Public Review):
The manuscript discussed the combination use of pyrotinib, tamoxifen, and dalpiciclib against HER2+/HR+ breast cancer cells. Through a series of in vitro drug sensitivity studies and in vivo drug susceptibility studies, the authors revealed that pyrotinib combined with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen. Moreover, the authors found that CALML5 may serve as a biomarker in the treatment of HER2+/HR+ breast cancer.
The authors provide solid evidence for the following:
- The combination use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen.
- Nuclear ER distribution is increased upon anti-HER2 therapy and could be partially abrogated by the treatment of …
Author Response
Reviewer #1 (Public Review):
The manuscript discussed the combination use of pyrotinib, tamoxifen, and dalpiciclib against HER2+/HR+ breast cancer cells. Through a series of in vitro drug sensitivity studies and in vivo drug susceptibility studies, the authors revealed that pyrotinib combined with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen. Moreover, the authors found that CALML5 may serve as a biomarker in the treatment of HER2+/HR+ breast cancer.
The authors provide solid evidence for the following:
- The combination use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen.
- Nuclear ER distribution is increased upon anti-HER2 therapy and could be partially abrogated by the treatment of dalpiciclib.
- CALML5 may serve as a putative risk biomarker in the treatment of HER2+/HR+ breast cancer.
The manuscript has significant strengths and several weaknesses. The strengths include the identification of the novel role of dalpiciclib in the treatment of HER2+/HR+ breast cancer. Moreover, the authors provide solid evidence that the combined use of dalpiciclib with pyrotinib significantly decreased the total and nuclear expression of ER. The main weakness of the manuscript is that the manuscript is difficult to read due to language inconsistency. In addition, some figure captions and figure legends should be carefully amended.
Thanks for your comments on our manuscript. We feel sincerely sorry for the inconsistency of the manuscript due to poor language. We have improved our manuscript as well as the figures according to your valuable suggestions.
Reviewer #2 (Public Review):
The authors performed preclinical studies to investigate the underlying mechanism of how the combination of pyrotinib, letrozole and dalpiciclib achieved satisfactory clinical outcomes in the MUKDEN 01 clinical trial (NCT04486911). Mechanistically, using anti-HER2 drugs such as pyrotinib and trastuzumab could degrade HER2 and facilitate the nuclear transportation of ER in HER2+HR+ breast cancer, which enhanced the function of ER signaling pathway. The introduction of dalpiciclib partially abrogated the nuclear transportation of ER and exerted its canonical function as cell cycle blockers, which led to the optimal cytotoxicity effect in treating HER2+HR+ breast cancer. Furthermore, using mRNA-seq analysis and in vivo drug susceptibility test, the authors succeeded in identifying CALML5 as a novel risk factor in the treatment of HER2+HR+ breast cancer.
Thanks for your comments and valuable suggestions, we’ve improved our manuscript according to your suggestions.
Reviewer #3 (Public Review):
In this research, the authors explore a novel mechanism of CDK4/6 inhibitor dalpiciclib in HER2+HR+ breast cancers, in which dalpiciclib could reverse the process of ER intra-nuclear transportation upon HER2 degradation. The conclusions are significant to gain insight into the biological behavior of TPBC and provided a conceptual basis for the ideal efficacy in the published clinical trial. The findings are supported by supplemented in vivo assay and transcriptomic analysis.
Thanks for your comments and valuable suggestions to us so that we could improve this manuscript.
-
eLife assessment
This study presents a valuable finding that the combined use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy against HER2+/HR+ breast cancer cells. The evidence supporting the claims of the authors is rather solid. The work will be of interest to medical biologists and clinical doctors working on breast cancer.
-
Reviewer #1 (Public Review):
The manuscript discussed the combination use of pyrotinib, tamoxifen, and dalpiciclib against HER2+/HR+ breast cancer cells. Through a series of in vitro drug sensitivity studies and in vivo drug susceptibility studies, the authors revealed that pyrotinib combined with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen. Moreover, the authors found that CALML5 may serve as a biomarker in the treatment of HER2+/HR+ breast cancer.
The authors provide solid evidence for the following:
1. The combination use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen.
2. Nuclear ER distribution is increased upon anti-HER2 therapy and could be partially abrogated by the treatment of dalpiciclib.
3. CALML5 …Reviewer #1 (Public Review):
The manuscript discussed the combination use of pyrotinib, tamoxifen, and dalpiciclib against HER2+/HR+ breast cancer cells. Through a series of in vitro drug sensitivity studies and in vivo drug susceptibility studies, the authors revealed that pyrotinib combined with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen. Moreover, the authors found that CALML5 may serve as a biomarker in the treatment of HER2+/HR+ breast cancer.
The authors provide solid evidence for the following:
1. The combination use of pyrotinib with dalpiciclib exhibits better therapeutic efficacy than the combination use of pyrotinib with tamoxifen.
2. Nuclear ER distribution is increased upon anti-HER2 therapy and could be partially abrogated by the treatment of dalpiciclib.
3. CALML5 may serve as a putative risk biomarker in the treatment of HER2+/HR+ breast cancer.The manuscript has significant strengths and several weaknesses. The strengths include the identification of the novel role of dalpiciclib in the treatment of HER2+/HR+ breast cancer. Moreover, the authors provide solid evidence that the combined use of dalpiciclib with pyrotinib significantly decreased the total and nuclear expression of ER. The main weakness of the manuscript is that the manuscript is difficult to read due to language inconsistency. In addition, some figure captions and figure legends should be carefully amended.
-
Reviewer #2 (Public Review):
The authors performed preclinical studies to investigate the underlying mechanism of how the combination of pyrotinib, letrozole and dalpiciclib achieved satisfactory clinical outcomes in the MUKDEN 01 clinical trial (NCT04486911). Mechanistically, using anti-HER2 drugs such as pyrotinib and trastuzumab could degrade HER2 and facilitate the nuclear transportation of ER in HER2+HR+ breast cancer, which enhanced the function of ER signaling pathway. The introduction of dalpiciclib partially abrogated the nuclear transportation of ER and exerted its canonical function as cell cycle blockers, which led to the optimal cytotoxicity effect in treating HER2+HR+ breast cancer. Furthermore, using mRNA-seq analysis and in vivo drug susceptibility test, the authors succeeded in identifying CALML5 as a novel risk factor …
Reviewer #2 (Public Review):
The authors performed preclinical studies to investigate the underlying mechanism of how the combination of pyrotinib, letrozole and dalpiciclib achieved satisfactory clinical outcomes in the MUKDEN 01 clinical trial (NCT04486911). Mechanistically, using anti-HER2 drugs such as pyrotinib and trastuzumab could degrade HER2 and facilitate the nuclear transportation of ER in HER2+HR+ breast cancer, which enhanced the function of ER signaling pathway. The introduction of dalpiciclib partially abrogated the nuclear transportation of ER and exerted its canonical function as cell cycle blockers, which led to the optimal cytotoxicity effect in treating HER2+HR+ breast cancer. Furthermore, using mRNA-seq analysis and in vivo drug susceptibility test, the authors succeeded in identifying CALML5 as a novel risk factor in the treatment of HER2+HR+ breast cancer.
-
Reviewer #3 (Public Review):
In this research, the authors explore a novel mechanism of CDK4/6 inhibitor dalpiciclib in HER2+HR+ breast cancers, in which dalpiciclib could reverse the process of ER intra-nuclear transportation upon HER2 degradation. The conclusions are significant to gain insight into the biological behavior of TPBC and provided a conceptual basis for the ideal efficacy in the published clinical trial. The findings are supported by supplemented in vivo assay and transcriptomic analysis.
-
