Synthetic lethality screening identifies 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.

Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

“…Moreover, it was shown that, in a breast cancer mouse model, tranilast treatment upregulates p53 and induces PARP and CASP3 cleavage in in vitro , consistent with the promotion of tumor cell apoptosis ( Subramaniam et al, 2010 ). In a recent work, through a synthetic lethality approach, the authors demonstrated that tranilast affects the expression of genes involved in several pathways that confer tolerance to cisplatin, including key platinum-transporting proteins such as ATOX1 ( Mariniello et al, 2020 ). In this regard, since Ca 2+ acts as a second messenger in several cell processes, gene expression modulation could reflect a TRPV2-mediated regulation of intracellular Ca 2+ levels ( De, 2011 ).…”

Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1

“…Studies have revealed a correlation between elevated ATP7B expression and reduced effectiveness of cisplatin chemotherapy in cancer patients ( Miyashita et al, 2003 ; Nakayama et al, 2004 ). Consequently, targeted downregulation of ATP7B expression and trafficking is currently being explored as a potential strategy to increase the efficacy of cisplatin therapy ( Mangala et al, 2009 ; Mariniello et al, 2020 ).…”

From and to the Golgi – defining the Wilson disease protein road map

“…In this case, it would be useful to develop an inhibitor, which affects both transporters, taking in account, however, that the impact of such inhibitor on the physiological functions of ATP7A and ATP7B has to be minimized. Interestingly, recent screening for FDA-approved drugs reducing tolerance to cisplatin revealed a compound, which suppresses ATOX1 expression and, as a consequence, ATP7B trafficking in a tumor-specific manner [61]. Considering that ATOX1 also supplies Cu/Pt to ATP7A, such compound would be promising for suppression of oncogenic activities of both ATP7A and ATP7B.…”