Universität zu Köln

Bartke, Leandra (2023). Drug combination studies of EZH2 inhibition combined with ATM, PI3-Kinase and CDK inhibitors in BRCA1-deficient breast tumors. PhD thesis, Universität zu Köln.

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Abstract

Current targeted treatment options for BRCA1-deficient breast cancer are limited. BRCA1-mutant breast cancers frequently show a triple-negative phenotype and are associated with poor survival. At the cellular level, BRCA1 is important for DNA double-strand break repair through the homologous recombination pathway. Our group previously showed that EZH2 is significantly higher expressed in BRCA1-associated breast tumors. EZH2, a member of the Polycomb repressive complex 2, acts as an epigenetic suppressor through its trimethyltransferase activity of H3K27me3, a modification associated with a variety of pathways involved in stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. To further exploit EZH2 overexpression upon Brca1-deficiency, we designed a large-scale cell line-based drug synergy screen using EZH2 inhibitor GSK126 in combination with different inhibitors involved in DNA damage signaling or cell cycle regulation. We made use of cell lines that were derived from Brca1-deficient (K14Cre;Brca1fl/fl;Tp53fl/fl) and Brca1-proficient (K14Cre;Tp53fl/fl) murine mammary tumors. Our screen revealed synergistic sensitivity of Brca1-deficient cells to treatment with the ATM inhibitor AZD1390, PI3K inhibitor BKM120 or CDK inhibitor dinaciclib combined with GSK126. Further validations by a variety of functional in vitro experiments showed significant growth inhibition and increased levels of unrepaired DNA damage upon treatment with the combination of GSK126 and AZD1390 in Brca1-deficient breast cancer cells indicating drug synergy. These findings could be confirmed for combined treatment with GSK126/AZD1390 in our Brca1-deficient murine model which show a significant survival benefit. Combined treatment of GSK126 and BKM120, as well as GSK126 and dinaciclib for Brca1-deficient breast cancer cells also demonstrated in vitro activity but were found to be of additive character. In summary, we hereby describe a novel synergistic combination treatment of GSK126/AZD1390 for the treatment of BRCA1-deficient breast cancer.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Bartke, Leandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-713814
Date:	2023
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Dissertation German
Date of oral exam:	7 August 2023
Referee:	Name Academic Title Reinhardt, Christian Universitätsprofessor Dr. med. Niessen, Carien Universitätsprofessorin Dr. PhD
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/71381