1. Cancer Biology

Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer

  1. Jiawen Bu
  2. Yixiao Zhang
  3. Nan Niu
  4. Kewei Bi
  5. Lisha Sun
  6. Xinbo Qiao
  7. Yimin Wang
  8. Yinan Zhang
  9. Xiaofan Jiang
  10. Dan Wang
  11. Qingtian Ma
  12. Huajun Li
  13. Caigang Liu  Is a corresponding author
  1. Shengjing Hospital of China Medical Universit, China
  2. Shengjing Hospital of China Medical University, China
  3. Jiangsu Hengrui Pharmaceuticals Co Ltd, China
https://doi.org/10.7554/eLife.85246
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Cite this article
  1. Jiawen Bu
  2. Yixiao Zhang
  3. Nan Niu
  4. Kewei Bi
  5. Lisha Sun
  6. Xinbo Qiao
  7. Yimin Wang
  8. Yinan Zhang
  9. Xiaofan Jiang
  10. Dan Wang
  11. Qingtian Ma
  12. Huajun Li
  13. Caigang Liu
(2023)
Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer
eLife 12:e85246.
https://doi.org/10.7554/eLife.85246
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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 were tested. The underlying molecular mechanisms were investigated using immunofluorescence, Western blot analysis, immunohistochemical staining and cell cycle analysis. Potential risk factor which 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.

Data availability

Sequencing data have been deposited in GSA database (https://ngdc.cncb.ac.cn/) under accession link: https://ngdc.cncb.ac.cn/omix/view/OMIX002504All data generated or analysed during the study are included in the manuscript and figure supplements.Source data files have been provided for Figure 1-Figure 4 as well as all the Figure supplements.Raw gel data for Figure 4 and Figure 2-figure supplement 1 was uploaded as source data files corresponding to the figures.

The following data sets were generated

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Author details

  1. Jiawen Bu

    Department of Oncology, Shengjing Hospital of China Medical Universit, Shenyang, China
    Competing interests
    No competing interests declared.

  2. Yixiao Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  3. Nan Niu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  4. Kewei Bi

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  5. Lisha Sun

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4095-5026

  6. Xinbo Qiao

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6759-921X

  7. Yimin Wang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  8. Yinan Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  9. Xiaofan Jiang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  10. Dan Wang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  11. Qingtian Ma

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Competing interests
    No competing interests declared.

  12. Huajun Li

    Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co Ltd, Shanghai, China
    Competing interests
    Huajun Li, is affiliated with Jiangsu Hengrui Pharmaceuticals Co. Ltd and the author has no other competing interests to declare..

  13. Caigang Liu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    For correspondence
    angel-s205@163.com
    Competing interests
    Caigang Liu, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2083-235X

Funding

National Natural Science Foundation of China (U20A20381)

  • Caigang Liu

National Natural Science Foundation of China (81872159)

  • Caigang Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The animal study was approved by the Ethics Committee of Shengjing Hospital of China Medical University (Permit Number: 2020PS318K). The pdf permission document have been uploaded as a Supporting Zip Document.

Copyright

© 2023, Bu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jiawen Bu
  2. Yixiao Zhang
  3. Nan Niu
  4. Kewei Bi
  5. Lisha Sun
  6. Xinbo Qiao
  7. Yimin Wang
  8. Yinan Zhang
  9. Xiaofan Jiang
  10. Dan Wang
  11. Qingtian Ma
  12. Huajun Li
  13. Caigang Liu
(2023)
Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer
eLife 12:e85246.
https://doi.org/10.7554/eLife.85246

Share this article

https://doi.org/10.7554/eLife.85246

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