Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.

Autor:	Ng V; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Sinha S; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Novaj A; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Ma J; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., McDermott N; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Pei X; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Longhini ALF; Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., Grimsley H; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Gardner R; Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York., Rosen E; Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Powell SN; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Pareja F; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Mandelker D; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Khan A; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Setton J; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Roulston A; REPARE Therapeutics, Saint-Laurent, Canada., Morris S; REPARE Therapeutics, Saint-Laurent, Canada., Koehler M; REPARE Therapeutics, Saint-Laurent, Canada., Lee N; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Reis-Filho J; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Riaz N; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 07, pp. OF1-OF14. Date of Electronic Publication: 2024 Aug 07.
DOI:	10.1158/1078-0432.CCR-24-0154
Abstrakt:	Purpose: The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase. Experimental Design: We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings. Results: Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients. Conclusions: Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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