Abstract 2684: Drug sensitivity profiling of BT-474 breast cancer cell line for identification of novel therapies targeting HER2-positive breast cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.2684-2684
• Main Authors: Mäki-Jouppila, Jenni H., Kähkönen, Tiina E., Suominen, Mari I., Halleen, Jussi M., Bernoulli, Jenni, Saarela, Jani, Fagerlund, Katja
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-2684

Developing 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 2 (HER2) is essential. However, breast cancer has high susceptibility to spread despite the targeted therapies and metastases often turn resistant to the used treatment. Therefore, new therapies are needed especially at the stage when cancer becomes resistant to hormonal therapy. The aim of the study was to investigate drug sensitivity of BT-474 breast cancer cell line and to recognize possible vulnerabilities especially in HER2+ breast cancer. BT-474 cell line (ER+, PR+, HER2+) is originally derived from human solid, invasive ductal carcinoma of the breast. Drug sensitivity of the cell line was assessed by screening of a large compound library consisting of many clinically available and emerging anti-cancer drugs including e.g. conventional chemotherapy, metabolic modifiers, kinesin inhibitors, apoptotic modulators, immunomodulators and kinase inhibitors such as HER2, pan-HER2 and EGFR-HER2 inhibitors. 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 pre-drugged 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 DSS (sDSS) was calculated to identify the selective drug response pattern. DSS analysis of BT-474 cell line showed sensitivity to conventional chemotherapy including paclitaxel and docetaxel and to kinase inhibitors such as EGFR and HER2 inhibitors neratinib, afatinib, mubritinib, poziotinib, dacomitinib and lapatinib with nanomolar EC50 values. Moreover, BT-474 cells showed sensitivity to PI3K and mTOR inhibitors, such as copanlisib and omipalisib, and to HSP90 and HDAC inhibitors, such as tanespimycin and abexinostat. Screening of large compound libraries combined with DSS and sDSS analysis enables drug sensitivity profiling of BT-474 breast cancer cells for discovery of novel therapies against HER+ breast cancer. Furthermore, drug sensitivity profiling enables repurposing of existing drugs to new indications and identification of vulnerabilities in different types of cancer cells. Citation Format: Jenni H. Mäki-Jouppila, Tiina E. Kähkö