Speaker: Ceyda Açılan
Title: Can we target epigenetic modifiers to revert drug resistance in prostate cancer?
Date/Time: 13 October 2021 / 13:40 - 14:30 PM
Abstract: Tumor resistance to chemotherapy is an emerging loss of efficacy of cytotoxic drugs. It is documented in all forms of cancer and against all forms of chemotherapy. Tumor resistance is unpredictable, difficult to model and a significant burden on drug development and cancer treatment. One of the mechanisms that drive gene expression changes leading to oncogenic transformation or drug resistance is through epigenetic regulations. Inhibition of epigenetic factors through small molecules have been shown to promote growth arrest and cell differentiation or apoptosis. Epigenetic drugs are usually not cytotoxic, and their promise is to prime the cells for subsequent therapies, usually by reprogramming cancer cells toward a normal state. Therefore, we exploited whether drug resistance could be overcome via targeting epigenetic modifiers. To answer this question, “Epigenetics Screening Library” and epi-targeted CRISPR dropout screens were performed in taxane-resistant prostate cancer cells that were generated in our laboratory. Interestingly, inhibition of some of the epi-targets, namely BRPF family proteins and PRMT5, consistently rescued the taxane resistance phenotype and were essential for the viability of resistant cells. The genetic interference and/or knock out of these genes confirmed the sensitization phenotype. Furthermore, silencing these genes lead to downregulation of ABCB1, which encodes a permeability glycoprotein (Pgp), and suppressed its function, potentially explaining how cells may be resensitized to taxane treatment. A compelling finding showed that while cells became resistant to taxanes, they were more susceptible to treatment with platinum drugs, which are not an ABCB1 substrate. Yet again, upon drug pressure, cisplatin resistance develops. Hence, in addition to ABCB1, we focus on the emerging idea that drug sequestration in the lysosomes followed by expulsion through lysosomal exocytosis (lysosomal flux) contributes to drug resistance in cancers. There is ample prior evidence that suppression of the lysosomal flux enhances the efficacy of frontline chemotherapeutics including cisplatin. This idea is unexplored with relation to epidrugs and is currently under investigation in our laboratory using prostate cancer cell line models. Our preliminary data show that most epidrugs increase lysosomal flux thereby may have failed in conjunction with frontline cytotoxic drugs in the clinic. We also identified a few drugs that decreased the flux, and indeed their combination enhanced the potency of cisplatin. Currently, we establish their mechanisms, which may serve as future targets for intervention in cancer.
Dr. Ceyda Açılan Ayhan graduated with honors from Bogaziçi University from the Department of Molecular Biology and Genetics in 2001. She earned her doctoral degree in 2006 at the University of Pittsburgh in the department of Molecular, Cellular and Developmental Biology, where she studied the role of DNA repair proteins in the formation of anaphase bridges under the supervision of Dr. William S. Saunders. She pursued her research interests as a postdoctoral associate at the University of Pittsburgh in the same laboratory and worked on how multipolar spindles are formed and whether cancer cells can be selectively killed using these segregation defects as a distinguishing factor. In 2008, Dr. Ayhan joined TUBITAK, Genetic Engineering and Biotechnology Institute as a Senior Researcher. She received her Chief Senior position in 2013 and her associate professorship in 2014. In 2018, she started to work as a faculty member at Koç University, in the School of Medicine. Her work is supported by several different sources, including 7th European Framework Programme, International Center for Genetic Engineering and Biotechnology (ICGEB), L’Oreal UNESCO, TUBITAK (1001, 1003 and 3501 programmes), Turkish Ministry of Health (TUSEB), Koc University-School of Medicine, Turkish Academy of Sciences (TUBA-GEBIP), Science Academy (BAGEP), and Eczacibasi Holding, a major Pharmaceutical company in Turkey. Currently, the ongoing projects in Ceyda ACILAN AYHAN laboratory try to address two main questions:
1. What are the mechanisms that cluster centrosomes and how can we selectively target cancer cells, which escape cell death via clustering their extra centrosomes?
2. Can we revert drug resistance / prime cancer cells for cell death through targeted inhibition of epigenetic modifiers? What are the molecular mechanisms involved in this process?