TY - JOUR TI - Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer AU - Bu, Jiawen AU - Zhang, Yixiao AU - Niu, Nan AU - Bi, Kewei AU - Sun, Lisha AU - Qiao, Xinbo AU - Wang, Yimin AU - Zhang, Yinan AU - Jiang, Xiaofan AU - Wang, Dan AU - Ma, Qingtian AU - Li, Huajun AU - Liu, Caigang A2 - Yang, Yongliang A2 - Zaidi, Mone A2 - Li, Huihui VL - 12 PY - 2023 DA - 2023/01/05 SP - e85246 C1 - eLife 2023;12:e85246 DO - 10.7554/eLife.85246 UR - https://doi.org/10.7554/eLife.85246 AB - 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. KW - breast cancer cell line KW - xenograft mouse model KW - patient specimens JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -