Synthetic lethality screening reveals FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

Abstract

Resistance of tumors to chemotherapy represents an important challenge in the modern oncology. Although platinum (Pt)-based drugs 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 copper-transporting ATPase, ATP7B. In fact, ATP7B expression has been identified as a hallmark of chemotherapy-resistant tumors. However, targeting the ATP7B for reduction of Pt-tolerance in tumors represents a serious risk because suppression of ATP7B might compromise copper homeostasis like it happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screening (HTS) of FDA/EMA-approved drug library to discover new therapeutic molecules that promote cisplatin toxicity in resistant ovarian carcinoma IGROV-CP20 cell line. Through a synthetic lethality approach, three hits (Tranilast, Telmisartan and Amphotericin B) were detected and validated for their ability to reduce cisplatin resistance. All 3 drugs induced DNA damage and inhibited ATP7B trafficking in a tumor-specific manner. RNAseq analysis revealed Tranilast and Amphotericin B to affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of copper and platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin. Considering well-known safety profiles and tolerability of Tranilast, Telmisartan and Amphotericin B these drugs emerge as attractive candidates, which might be used for rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.