Abstract 1790: Herceptin-resistant breast cancer cells exhibits distinct sensitivity to lapatinib in in vivo tumor xenograft models

Abstract

Abstract Introduction: HER2-targeted therapies, including the monoclonal antibody (Ab) herceptin and the tyrosine kinase inhibitor (TKI) lapatinib, have been commonly used to treat HER2-positive breast cancer (BC). However, resistance to herceptin and/or lapatinib frequently occurs and currently represents a significant clinical problem. We previously demonstrated that both HER3- and IGF-1 receptor (IGF-1R)-initiated signaling played crucial roles in the development of herceptin resistance. Further studies showed that our herceptin-resistant SKBR3-pool2 and BT474-HR20 sublines, as compared their parental SKBR3 and BT474 cells, respectively, also exhibited refractoriness to lapatinib in vitro. However, the in vivo efficacy of lapatinib against the herceptin-resistant BC models (SKBR3-pool2 and BT474-HR20) remains unclear. Methods: Tumor xenograft models were established via subcutaneous inoculation of SKBR3-pool2 or BT474-HR20 cells into athymic nude mice. Tumor formation was assessed by palpation and measured with fine calipers twice a week. The tumor-bearing mice were treated with vehicle (DMSO) or lapatinib (80 mg/kg) via intraperitoneal injection daily for three weeks. Immunohistochemistry (IHC) assays were performed to assess the expression and activation of proteins. Two individuals independently read and quantified all IHC slides by considering both the intensity of immunostaining and the percentage of positive-staining tumor cells. Results: Treatment with lapatinib profoundly inhibited growth of the tumors established with SKBR3-pool2 cells. In contrast, lapatinib slightly, but not significantly, reduced tumor growth in BT474-HR20 cells-derived xenograft models. IHC analyses of the tumors obtained from both SKBR3-pool2 and BT474-HR20 xenografts showed that lapatinib treatment had little effect on the expression of HER3 and the protein phosphatase PPP3CB. Lapatinib also did not alter the levels of phosphorylated Akt (p-Akt) and FOXO3a (p-FOXO3a) in vivo. Interestingly, in BT474-HR20-derived tumors, lapatinib treatment dramatically enhanced expression of insulin receptor substrate-1 (IRS1) and increased the levels of phosphorylated HER3 (p-HER3). However, such phenomena were not observed in the tumors established with SKBR3-pool2 cells. Conclusion: While the tumors derived from BT474-HR20 cells retain their resistant phenotype to lapatinib, SKBR3-pool2-tumors are highly sensitive to lapatinib treatment. It seemed that lapatinib-induced upregulation of IRS1 and activation of HER3, evidenced by increased p-HER3, contributed to the inefficacy of lapatinib against BT474-HR20-tumors in vivo. Keywords: HER3, IRS1, treatment resistance, HER2-targeted therapy, breast cancer Citation Format: Sanbao Ruan, Hao Liu, Hui Lyu, Congcong Tan, Bolin Liu. Herceptin-resistant breast cancer cells exhibits distinct sensitivity to lapatinib in in vivo tumor xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1790.