Abstract A151: Drug sensitivity profiling of BT-474 breast cancer cell line for identification of novel therapies against HER2-positive breast cancer

Abstract

Abstract Introduction: Targeted therapy for breast cancer expressing hormone receptors such as estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor receptor (HER2), is essential. In spite of current targeted therapies, breast cancer has high susceptibility to spread and metastases often turn resistant to the used treatment. Therefore, new therapies are needed, especially when cancer becomes resistant to hormonal therapy. The aim of the study was to investigate drug sensitivity and resistance of BT-474 breast cancer cell line and to recognize possible vulnerabilities, especially in hormone therapy resistant HER2+ breast cancer. Materials and Methods: BT-474 cell line (ER+, PR+, HER2+) is originally derived from human solid, invasive ductal carcinoma of the breast. The drug sensitivity of the cell line was assessed by applying a large panel of drugs covering cancer chemotherapeutics and clinically available and emerging drugs including, e.g., conventional chemotherapy and kinase inhibitors such as HER2, pan-HER2, and EGFR-HER2 inhibitors. Altogether a panel of 525 compounds was tested in five concentrations covering a 10,000-fold drug-relevant concentration range in 384-well format. Cells were seeded to predrugged plates, followed by cell viability measurements (CellTiter-Glo) after 72 hours. Maximal and minimal responses to drugs were analyzed, the EC50 values were calculated, and Drug Sensitivity Score (DSS) was calculated for each drug as a measure of reduced viability. A selective Drug Sensitivity Score (sDSS) was calculated to identify the selective drug response pattern. Results: DSS analysis of BT-474 cell line showed sensitivity to conventional chemotherapy including paclitaxel and docetaxel and to kinase inhibitors such as EGFR inhibitors neratinib and afatinib. In the absence of supplemented estradiol, the cell line was not sensitive to hormonal therapies, including antiestrogens and selective estrogen receptor modulators. However, BT-474 cells were sensitive to HER2, pan-HER2, and EGFR-HER2 inhibitors including mubritinib, poziotinib, dacomitinib, and lapatinib with EC50 range from 2 to 98 nM. The BT-474 cells also showed sensitivity against PI3K and mTOR inhibitors, such as copanlisib and omipalisib. Conclusions: Screening of large compound libraries combined with DSS and sDSS analysis enables drug sensitivity profiling of HER2+ BT-474 breast cancer cells for identification of novel anticancer compounds against breast cancer, especially for the hormonal-resistant stage of the disease. Moreover, the assay enables repurposing of existing drugs to new indications, identification of vulnerabilities in different types of cancer cells, and functional investigation of cellular pathways behind drug sensitivity or resistance. Citation Format: Jenni Mäki-Jouppila, Tiina Kähkönen, Mari I. Suominen, Katja M. Fagerlund, Jussi M. Halleen, Jani Saarela, Jenni Bernoulli. Drug sensitivity profiling of BT-474 breast cancer cell line for identification of novel therapies against HER2-positive breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A151.