October 16, 2020 at 15:00
“ATP7B vs cisplatin”
Dr. Roman Polishchuk, PhD
Head of Advanced Microscopy and Imaging Core TIGEM (Telethon Institute of Genetics and Medicine)
Host: Prof. Luisa Rossi
Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.
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Born in 1970 in Ivanovo, Russia, Roman Polishchuk graduated in Biology from Ivanovo State University. After a post-doc experience at the Mario Negri South Consortium of Santa Maria Imbaro (CH), Roman Polishchuk worked in the USA as an associate researcher at the National Institutes of Health in Bethesda. Back in Italy at the Mario Negri Sud Consortium, he then moved to the Telethon Institute of Genetics and Medicine (Tigem) in Naples, where he is still head of the Electron Microscopy Facility. With his research group, Roman Polishchuk studies the molecular mechanisms underlying Wilson’s disease, a rare liver disease characterized by an excessive accumulation of copper (CV from Telethon.it).