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Review
. 2023 Apr;21(2):203-207.
doi: 10.1016/j.clgc.2022.10.016. Epub 2022 Nov 4.

ATR Inhibition in Advanced Urothelial Carcinoma

Ryan C Leibrandt  1 , Mei-Juan Tu  2 , Ai-Ming Yu  2 , Primo N Lara  3 , Mamta Parikh  4
Affiliations
Review

ATR Inhibition in Advanced Urothelial Carcinoma

Ryan C Leibrandt et al. Clin Genitourin Cancer. 2023 Apr.

Abstract

The ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase 1 (CHK1) pathway is intricately involved in protecting the integrity of the human genome by suppressing replication stress and repairing DNA damage. ATR is a promising therapeutic target in cancer cells because its inhibition could lead to an accumulation of damaged DNA preventing further replication and division. ATR inhibition is being studied in multiple types of cancer, including advanced urothelial carcinoma where there remains an unmet need for novel therapies to improve outcomes. Herein, we review preclinical and clinical data evaluating 4 ATR inhibitors as monotherapy or in combination with chemotherapy. The scope of this review is focused on contemporary studies evaluating the application of this novel therapy in advanced urothelial carcinoma.

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Conflict of interest statement

Disclosure The authors have no conflicts of interest to report

Figures

Figure 1
Figure 1
ATM and ATR in the DNA damage response system
Figure 2
Figure 2
ATR inhibitors under clinical development
Figure 3
Figure 3
Combination of elimusertib and platinum chemotherapy synergistically inhibits the proliferation of human bladder cancer cells. Human bladder cancer 5637 (A-C) and T24 (D-F) cells were treated with various concentrations of elimusertib alone, cisplatin or carboplatin alone, or the combination of elimusertib and cisplatin/carboplatin for 72 h, and cell viability then was determined by MTT assay. Elimusertib alone, cisplatin (A & D) or carboplatin (B & E) alone, and the combination of elimusertib and cisplatin/carboplatin exhibited dose-dependent effects in the inhibition of bladder cancer cell viability. Combination treatments showed stronger efficacy than the corresponding single drug treatments in both cell lines. Values are mean ±SD (N = 5/group). (C & F) Combination index (CI) versus Fraction affected (Fa) plots revealed a synergism for the combination of elimusertib and cisplatin/carboplatin in suppressing bladder cancer cell viability
See this image and copyright information in PMC

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