Dalpiciclib Partially Abrogates ER Signaling Activation Induced by Pyrotinib In HER2⁺HR⁺Breast Cancer

AbstractBackgroundRecent evidences from clinical trials (NCT04486911) revealed that the combination of pyrotinib, letrozole and dalpiciclib exerted optimistic therapeutic effect to treat HER2+HR+breast cancer, however, the underlying molecular mechanism remained further investigation.MethodsThrough 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 selected out using RNA-sequence and tested using immunohistochemical staining and in vivo drug susceptibility test.ResultsWe 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 this.ConclusionOur 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.FundingThis study was supported by the National Natural Science Foundation of China (#U20A20381, #81872159)