Abstract 5335: Discovery and validation of new kinase targets for therapy in ovarian clear cell cancer

Abstract

Abstract Introduction: Ovarian clear cell carcinoma is less responsive to chemotherapy and has a worse prognosis than other ovarian cancer subtypes. The most frequently mutated genes in ovarian clear cell carcinoma have been characterized in recent years. Mutations include deleterious mutations in the tumor suppressor gene ARID1A, epigenetic silencing and deleterious mutations in the PI3K antagonist PTEN, as well as activating mutations in the PI3K catalytic subunit PIK3CA. Yet, therapeutic strategies that utilize these genetic aberrations are lacking. In the present study, we aimed to identify and validate new kinase targets in ovarian clear cell carcinoma. Methods: To determine new mutations, kinome sequencing (SureSelect Human Kinome Kit, Agilent Technologies) was performed on DNA isolated from tumor samples (n = 124) and matched controls (n = 46) for 571 kinases, 6 PI3K regulatory components and 46 other cancer related genes. In addition, to identify gene copy number gains and losses, high-throughput SNP analysis (HumanOmniExpressExome-8 Illumina SNP array) were analyzed in 109 ovarian clear cell carcinoma tumor samples. Results: Preliminary results revealed mutations in PIK3CA (43.5%), PTEN (6.5%), KRAS (15.3%) and TP53 (11.3%), which correspond to frequencies found in literature. Most mutations were found in genes encoding PI3K/Akt and MAPK signal transduction pathway, DNA repair pathway, and receptor tyrosine kinase signaling pathway components. Mutations in these pathways were present in 75% of ovarian clear cell carcinomas, while 42% of the patients had mutations in ≥ 2 of these pathways. Profiles of copy number gains and losses matched previous studies. Most interestingly, however, we also discovered multiple novel kinase mutations and identified new chromosomal regions of copy number gains and losses. Conclusion: Combining high-throughput SNP analysis and kinome sequencing allowed us to identify novel mutations, copy number gains and losses in kinases and other cancer related genes. Currently we are re-sequencing the most interesting kinase mutations using Sanger sequencing. Subsequent validation of the therapeutic value of new targets will be assessed in vitro using a large ovarian clear cell carcinoma cell line panel followed by in vivo validations. Supported by a grant from the Dutch Cancer Foundation: RUG 2012-5477 Citation Format: Joseph J. Caumanns, Steven de Jong, G. Bea A. Wisman, Pieter Van der Vlies, Roel J.C. Kluin, Lorenza Mittempergher, Katrien Berns, René Bernards, Ate G.J. Van der Zee, The ovarian clear cell cancer consortium. Discovery and validation of new kinase targets for therapy in ovarian clear cell cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5335. doi:10.1158/1538-7445.AM2015-5335