Abstract 1787: Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer

Abstract

Abstract Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) are a widely successful strategy for the treatment of HER2-positive breast cancer. Despite the demonstrated efficacy, intrinsic and acquired resistance to anti-HER2 ADCs remains a major challenge. The activity of ADCs is dependent upon the internalization of the HER2-ADC complex into specific subcellular compartments permissive for release of the chemotherapeutic payload. Previous studies have demonstrated that statins, a commonly used cholesterol-lowering medication, could increase plasma membrane-bound HER2 and improve trastuzumab efficacy in HER2-positive gastric cancer. In this study, we sought to characterize the impact of statins on the efficacy of HER2 ADCs. We performed in vitro internalization assays with trastuzumab emtansine (T-DM1) labeled with a pH-sensitive pHrodo fluorogenic dye to monitor T-DM1 entering lysosome whereupon payload DM1 is released, and found that combined treatment of T-DM1 and lovastatin potently enhanced T-DM1 internalization of T-DM1 into lysosome in HER2-amplified and HER2-low models. Consistent with the internalization assays, lovastatin increased cell death caused by T-DM1 and sensitized the HER2-low ZR75-1 cells to T-DM1 treatment in vitro. Using HER2-positive xenograft models, we found orally administrated lovastatin promoted T-DM1 uptake in tumors and enhanced T-DM1 efficacy in vivo. To investigate whether these results might be observed in the clinic, we conducted retrospective analyses on a cohort of 164 HER2 positive metastatic breast cancer patients treated at MSKCC who received T-DM1. Among these patients, 21 (12.8%) were taking statins concurrently with T-DM1, and the median progression-free survival in the patients who received statins was 14 months (95% confidence interval, 3.5-24 months) compared to 5.4 months (95% confidence interval, 3.9-7.0 months) in those who had no record of statin use (p=0.1). Overall, our findings demonstrate that statins potentiate the susceptibility of breast cancer cells to anti-HER2 ADCs by modulating HER2 membrane dynamics and HER2-ADC internalization, suggesting statin as a rational therapeutic partner for anti-HER2 ADC in HER2-positive breast cancer, especially those with relatively low HER2 expression. Citation Format: Bo Liu, Joshua Z. Drago, Yi Rao, Patricia R. Pereira, Anton Safonov, Antonio Marra, Mehnaj S. Ahmed, Shanu Modi, Jorge S. Reis-Filho, Filippo Montemurro, Pedram Razavi, Jason S. Lewis, Sarat Chandarlapaty. Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer [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 1787.