Combination therapy of the EZH2 inhibitor GSK126 and the PARP inhibitor Olaparib shows in vivo synergy in a patient-derived xenograft model of BRCA1-deficient breast cancer

Abstract

Background: Current treatment options for BRCA1-deficient breast cancer are limited highlighting the need for novel targeted therapies. Our group previously demonstrated that EZH2 is overexpressed in BRCA1-deficient breast tumors and a promising target for this subtype. EZH2 is the catalytic subunit of polycomb repressive complex 2 and involved in gene silencing through methylation of histone H3K27. Recently, GSK126, a highly selective inhibitor of EZH2 methyltransferase activity, was discovered. Additionally, PARP inhibitors are effective in breast tumors with defects in homologous recombination due to BRCA1 mutations. Methods: To study a possible synergy between the EZH2 inhibitor GSK126 and PARP inhibitor Olaparib we made use of a patient-derived xenograft (PDX) model from triple negative breast cancer with BRCA1 mutation. Cell lines were derived from a genetically modified mouse model for hereditary breast cancer (K14cre;Brca1F/F;p53F/F). Results: Combined inhibition of EZH2 and PARP in BRCA1-deficient cell lines resulted in delayed cell growth compared to single treatments. In the BRCA1-deficient PDX model the EZH2 inhibitor GSK126 alone attenuated the tumor growth modestly. Treatment with Olaparib shows tumor stasis. However, dual EZH2 and PARP inhibition with GSK126 and Olaparib reduced the tumor volume substantially. Western blot analysis of tumor lysates demonstrate target inhibition of GSK126 by significantly reduced H3K27me3-levels. Conclusion: Here, we report that the combination of EZH2 inhibition with a PARP inhibitor provides in vivo synergy in a PDX-mouse model for BRCA1-deficient breast tumors. Our findings suggest that this candidate combination might be an effective treatment of BRCA1-related tumors to be tested in further trials.