Identifying Ovarian Cancer Specific Targeted Drugs Using High-Throughput Drug Sensitivity Profiles Of Primary Cancer Cells

Ovarian cancer (OvCa) is the sixth most common cancer in women and leading cause of death from gynecologic diseases. Poor prognosis in OvCa is due to late diagnosis and acquired resistance to the commonly used platinum-based regimens. A significant setback for OvCa treatment is the lack of reliable biomarkers and effective targeted therapies. In order to discover novel therapeutic opportunities with approved and emerging drugs for OvCa, we have established primary cultures using ascites or tumor tissue samples from chemo-refractory ovarian cancer patients for ex vivo Drug Sensitivity and Resistance Testing (DSRT) and genomic profiling. In addition, we have performed DSRT with 31 established OvCa cell lines. Comparison of the drug sensitivity profiles of ten primary cancer cell cultures and 31 OvCa cell lines revealed previously unanticipated cancer selective drug vulnerabilities. Several drug groups were identified suggesting that the sensitive samples were addicted to the corresponding signaling networks. For example, in a 53-year old chemorefractory low grade serous OvCa patient, genomic and transcriptomic analyses revealed a fusion gene of NRG-1, a target that was recently reported to involve the NRG1/ERBB3 activation loop in OvCa. We found high expression of ERBB2 and ERBB3 by RNA-seq as well as high levels of phospho-ERBB3, phospho-ERBB2 and phospho-EGFR by immunohistochemistry. In agreement with the molecular mechanism, DSRT analysis identified significant sensitivity of primary cancer cells to EGFR inhibitors, such as erlotinib and to dual EGFR and Her2 inhibitor afatinib. The patient has received combination therapy of gemcitabine and erlotinib during nine months, followed by afatinib monotheraphy that has lead to complete remission after six months treatment. We have detected activated NRG1/ERBB3 activation loop also in several additional ovarian cancer patient cases, highlighting the importance of this signaling pathway in ovarian cancer pathogenesis. Our study reveals that a subset of serous ovarian cancer patients with activating NRG1/ERBB3 signaling loop have clinical benefits from repurposing dual EGFR/Her2 inhibitor afatinib, providing a basis for the clinical use of EGFR and dual EGFR/Her2 tyrosine kinase inhibitors in clinical treatment. In conclusion, DSRT technology together with molecular profiling provides a powerful strategy to identify tumor driver signals and select clinically actionable inhibitors. Hence, this type of systems medicine approach can significantly improve the power of mainly genomics-oriented personalized medicine approaches. Citation Format: Astrid Murumagi, Akira Hirasawa, Suleiman Khan, Daniela Ungureanu, Mariliina Arjama, Teijo Pellinen, Samuli Eldfors, Riitta Koivisto-Korander, Arto Leminen, Ralf Butzow, Tero Aittokallio, Olli Kallioniemi. Identifying ovarian cancer specific targeted drugs using high-throughput drug sensitivity profiles of primary cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2017-410