Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer
- Shengjing Hospital of China Medical Universit, China
- Shengjing Hospital of China Medical University, China
- Jiangsu Hengrui Pharmaceuticals Co Ltd, China
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.
Article and author information
Author details
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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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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