Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers
Marta MarinielloRoman Polishchuk

Abstract

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 oper...Continue Reading

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Citations

Jul 17, 2020·International Journal of Molecular Sciences·Maria C Linder
Oct 23, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Bangxing HongBalveen Kaur
Jun 1, 2021·Seminars in Cancer Biology·Fabio Arnesano, Giovanni Natile
Jun 27, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Soha OsmanSaid Dermime
Jun 23, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·David LukanovićKatarina Černe

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Datasets Mentioned

BETA
GSE134029

Methods Mentioned

BETA
dot
ubiquitination
dot blot
PCR
Assay
dot immuno-blot
transfection
Fluorescence

Software Mentioned

ImageJ
QuantSeq

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