Dalpiciclib synergizes with pyrotinib to inhibit HR−/HER2+ breast cancer via CTGF targeting in the hippo pathway

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The efficacy of pyrotinib monotherapy in HER2-positive breast cancer cells is limited, exhibiting a low response rate. Prolonged exposure to pyrotinib induces drug resistance. As downstream effectors of HER2 signaling, CDK4/6 contribute to resistance against HER2-directed therapies. Conversely, combination therapy significantly improves drug efficacy and extends the duration of treatment. To evaluate whether combining the CDK4/6 inhibitor dalpiciclib with pyrotinib enhances antitumor activity and to elucidate the underlying molecular mechanisms, two HER2-enriched breast cancer cell lines (SKBR3 and AU565) were treated with dalpiciclib, pyrotinib, or their combination. Antitumor activity was assessed via MTT assay, colony formation, wound healing, cell invasion assays, and xenograft models. Combination index analysis showed CI values below 1, supporting a synergistic interaction between dalpiciclib and pyrotinib. Bioinformatic analysis of pyrotinib-resistant and parental HER2-positive cells identified differentially expressed genes associated with Hippo pathway alterations, with CTGF expression significantly decreased in resistant cells. Co-immunoprecipitation assays suggested an association between OTUD1 and YAP under overexpression conditions. In xenograft tissues, combination treatment was associated with YAP downregulation and CTGF elevation. These findings suggest that dalpiciclib may enhance the antitumor effect of pyrotinib in HER2-positive/HR-negative breast cancer, partly through modulation of the OTUD1/YAP/CTGF axis.

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