We acknowledge support from TUBITAK, Science Academy BAGEP and European Cooperation in Science and Technology (COST).
Targeting CDK4/6 signalling in Ovarian Cancer.
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental regulators of G1-S transition checkpoint in cell cycle. CDK4/6 signalling pathways are dysregulated in various cancer types by means of genetic and epigenetics mechanisms. Hence, data mining efforts through TCGA database demonstrated dysregulation of CDK4/6 pathway in nearly 40% of serous epithelial ovarian cancers. As a result of intense efforts on developing CDK4/6 small molecule inhibitors for cancer therapeutics, CDK4/6 inhibitors palbociclib and ribociclib were approved by FDA in ER+/HER2-breast cancer patients in combination with anti-estrogen therapy. Abemaciclib is another small molecule CDK4/6 inhibitor which was designated “Breakthrough Therapy” in breast cancer by FDA and currenlty being evaluated in Phase III trials. In this project, we aim to systematically identify the mechanisms mediating the effect of target kinases identified by highthroughput RNAi screen, by which inhibition of these kinases led to cell death instead of supression of proliferation and cell cycle progression when combined with CDK4/6 inhibitor abemaciclib.
Mitochondrial Estrogen Receptors in Breast Cancer
How do mitochondrial estrogen receptors (ERs) affect mitochondrial priming and chemotherapy response in breast cancer cells? In this project, we try to understand how mitochondria-localized ERs in ER (+) breast cancer cells modulate mitochondrial priming preset and Bcl-2 protein dependence of these cells. In addition, response to physiologic and chemical cell death inducers are currently being evaluated in mitochondrial-ER (+) and (-) cells. BH3 profiling technique developed in Letai Lab has been adapted into the lab routine and in parallel, a BH3 signature is being sought for ER-negative breast cancer cell lines.
Targeting Rab25 GTPase in Ovarian Cancer
This project aims to identify the role of a small Rab GTPase, Rab25, in the pathobiology of ovarian cancer. An ovarian cancer cell line panel is being used as the initial experimental model, focusing on how this small Rab GTPase regulates cell cycle progression, cell death and cell proliferation in ovarian cancer cells in addition to its vesicle trafficking function. Protein knockdown/overexpression studies, fluorescence proliferation assays, immunofluorescence confocal microscopy, cell cycle and cell death assays are being utilized as fundamental experimental approaches.
Resistance to pan-HER inhibitors in Breast Cancer
While several panHER inhibitors are currently being developed for the treatment of various human cancers including breast cancer, we still don’t have enough insight into the molecular switches how cancer cells become resistant to panHER inhibition. In this project, we tackle the question how HER2+ breast cancer cells acquire resistance to panHER inhibitor neratinib, regarding the cellular signaling pathways governing HER signaling and mitochondrial apoptosis.
