Abstract 4593: Inhibition of invasion of HER2-positive breast cancer cells by lysosome targeting drugs

Abstract

Abstract Up to 20% of all breast cancers are over-expressing HER2/ErbB2, leading to malignant and invasive cancers with a poor patient outcome. Though good ErbB2-targeting treatments have been developed, metastasis formation and drug resistance are still major challenges for the long-term cure. This project aims to find out if some of the numerous pre-existing compounds and clinically approved drugs can be repurposed to treat or improve the treatment of HER2/ErbB2-positive breast cancer. We have therefore set up a high-throughput and high-content screen of the Prestwick Chemical Library to identify drugs that can reverse the ErbB2-induced, invasion-promoting, peripheral distribution of lysosomes. Using a breast cancer cell model expressing N-terminally truncated version of ErbB2, we mimic breast cancer that is resistant to the currently used antibodies, trastuzumab and pertuzumab. This cell line shows a highly invasive phenotype with increased activation of the lysosomal proteases, cysteine cathepsin B and L, as well as anterograde movement of lysosomes. This repositioning of the lysosomes enables them to fuse with the plasma membrane and empty their acidic and hydrolyzing content to the extracellular matrix, promoting invasion. Treatment with the clinically used drug lapatinib will reverse this phenotype. The cells ability to reverse the phenotype, through increasing the number of perinuclear lysosomes while removing lysosomes form cellular protrusions, was evaluated for each screened drug, using the ImageXpress Micro Confocal High-Content Imaging System. We have hereby identified eight drugs that can redirect lysosomes from the invadosome-like cellular protrusions to their non-invasive perinuclear position in ErbB2 expressing breast cancer cells. We are currently analyzing the impact of these drugs on breast cancer cell invasion though migration assays and three-dimensional invasion assays. We are also addressing their effect on lysosomal membrane permeabilization, lysosomal pH and investigating their effect on proteins that are known to be involved in lysosomal distribution. Clinically, our findings may facilitate repurposing or new development of drugs to treat HER2/ErbB2-positive and invasive breast cancers that are resistant to current treatments. Citation Format: Malene B. Hansen, Maria Postol, Davig A. Egan, Marja Jäättelä, Tuula Kallunki. Inhibition of invasion of HER2-positive breast cancer cells by lysosome targeting drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4593.