Abstract 2107: Identification of alternative compounds by drug screening of HER2 positive breast cancer cell lines.
Authors: Nyberg Sandra , Hongisto Vesa , Shiferaw Tadele Dagim , Edgren Henrik , Leivonen Suvi-Katri , Kallioniemi Olli , Mælandsmo Gunhild Mari , Perälä Merja , Børresen-Dale Anne-Lise , Kleivi Sahlberg Kristine 
Published: August 2014

About 15% of the diagnosed breast cancers have an amplicon in the 17q12-21 region leading to over-expression of the human epidermal growth factor receptor 2 (HER2). HER2 activates two main downstream pathways, the PI3K/Akt and the MAPK pathways, that are involved in survival, cell growth and proliferation. HER2 positive (HER2+) breast cancers are treated with trastuzumab or lapatinib, which inhibit HER2 by different molecular mechanisms. However, many patients develop resistance or do not respond to the treatment. Therefore, identification of alternative compounds that could replace the current treatment strategies in the patients who have developed resistance is vital.

Thirteen HER2+ breast cancer cell lines were screened with 22 compounds targeting the EGFR family pathways, or other key players in the HER2+ breast cancers. The compounds were printed in seven concentrations in two replicates and all screens were performed twice. Cell viability was used as an endpoint. In addition, gene expression profiles, copy number changes and PIK3CA mutation status, as well as PTEN protein expression levels were analyzed for the same cell lines.

Thirteen compounds induced more than 50% growth inhibition with the highest concentration for two or more cell lines and were selected for further analyses. All EGFR-family targeting inhibitors were more effective in the trastuzumab-responsive than in the non-responsive cell lines. In addition, several other drugs also inhibited cell growth more efficiently than trastuzumab.

The cell lines were divided into three groups based on their response to trastuzumab: responsive, intermediate, and non-responsive. Similarly, three response groups were seen for lapatinib, but they did, however, not have a complete overlap with the trastuzumab response groups. These groups were used to find drugs that are effective in the resistant cell lines. Interestingly, two mTOR inhibitors, everolimus and temsirolimus, were most effective in trastuzumab-resistant cell lines. In addition, two trastuzumab-resistant cell lines were more sensitive to an Akt inhibitor than the rest of the cell lines. These findings will be further validated by comparing gene expression and mutation statuses of these cell lines to others.

In conclusion, compound screening revealed several inhibitors that efficiently decreased cell viability in HER2+ cell lines. Interestingly, Akt and mTOR inhibitors decreased cell growth in cell lines that did not respond to the inhibitors currently used in the clinic. To understand the molecular mechanisms of the drug actions, further studies at the genomic levels are needed.

Citation Format: Sandra Nyberg, Vesa Hongisto, Dagim Shiferaw Tadele, Henrik Edgren, Suvi-Katri Leivonen, Olli Kallioniemi, Gunhild Mari Mælandsmo, Merja Perälä, Anne-Lise Børresen-Dale, Kristine Kleivi Sahlberg. Identification of alternative compounds by drug screening of HER2 positive breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2013-2107