ATR Inhibition in Advanced Urothelial Carcinoma

Leibrandt, Ryan; Tu, Meijuan; Yu, Alice L.; Lara, Primo N.; Parikh, Mamta

doi:10.1016/j.clgc.2022.10.016

Cited by 3 publications

(2 citation statements)

References 35 publications

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“…This approach is believed to hold promise, as preclinical studies have indicated that it could enhance the effectiveness of chemotherapy by increasing DNA damage and cell death in cancer cells. Further clinical trials are needed to confirm these findings, but they offer a hopeful avenue for the development of more potent treatments for urothelial carcinoma [51].…”

Section: Discussionmentioning

confidence: 99%

Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process

Xiao

Huang

et al. 2023

Cells

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Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant TP53 UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process

Xiao

Huang

et al. 2023

Cells

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“…ATR inhibitor AZD6738 has been proven to synergize with chemotherapy agents like cisplatin in various solid tumor preclinical models, resulting in augmented antitumor activity [ 105 , 117 ]. Likewise, berzosertib (VE-822, VX-970, M6620) has been found to increase cell death both in cell lines and in patient-derived primary lung xenografts after cisplatin treatment while also exhibiting a strong effect in tumor growth arrest in NSCLC models [ 118 , 119 ]. Other chemotherapy drugs may also be combined with ATR inhibition.…”

Section: The Atr Pathway As a Therapeutic Targetmentioning

confidence: 99%

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

Mavroeidi,

Georganta,

Panagiotou

et al. 2024

IJMS

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The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

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New Horizons in Lung Cancer Management Through ATR/CHK1 Pathway Modulation

Thapa,

Afzal,

Bhat

et al. 2023

Future Med. Chem.

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Lung cancer is the leading cause of cancer-related deaths worldwide. Molecular profiling has contributed to a new classification of lung cancer, driving advancements in research and therapy. The ataxia telangiectasia and rad3/checkpoint kinase 1 (ATR/CHK1) pathway plays a crucial role in maintaining genomic stability, and its activation has been linked to the development of lung cancer, drug resistance and poor prognosis. Clinical and preclinical studies have demonstrated promising results in targeting this pathway. ATR and CHK1 are proteins that collaborate to repair DNA damage caused by radiation or chemotherapy. ATR/CHK1 inhibitors are currently under investigation in preclinical and clinical trials. This article explores the ATR/CHK1 pathway and its potential for treating lung cancer.

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ATR Inhibition in Advanced Urothelial Carcinoma

Cited by 3 publications

References 35 publications

Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process

Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

New Horizons in Lung Cancer Management Through ATR/CHK1 Pathway Modulation

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