Abstract A004: Radiotherapy sensitizes preclinical models to DNA damage response agents
Authors: Binder Pablo , Katopodi Theoni , Hanson Lyndsey , Bell Charlotte R. , Flanagan Eimear , Farrington Paul , Moore Nick , Wright Emily , Ho Yin Xin , Bunday Tobias , Brown Stewart , Cantrell Amy , Mamane Yael , Greenall Jon , Sharman Shannon , Woolley John , Mooney Lorraine M. , Kendrew Jane 
Published: June 2024

Abstract
Introduction Radiotherapy is a key treatment for various cancers, with nearly 50% of all cancer patients receiving it as part of their therapeutic plan. It can activate cytotoxic signaling pathways to promote cancer cell death but also trigger cytoprotective mechanisms that respond to cellular damage. These cytoprotective mechanisms can be inhibited by targeted anticancer agents such as DNA damage response (DDR) agents, suggesting that radiotherapy could enhance the efficacy of these drugs. This study presents data showing radiotherapy enhances the potency of DDR agents in preclinical models. Methods and experimental procedures The MDA-MB-436 breast and A549 lung cancer cell lines were utilized to establish in vitro assays and in vivo models for the study. Agents targeting DNA-PK (AZD7648) and PARP (niraparib) were used as they work on pathways crucial for the repair of radiation-induced DNA double-strand breaks. The effects on cell viability and DDR biomarkers were assessed after treatment with irradiation (IR), compound or in combination both in vitro and in vivo. Targeted X-rays were delivered using an Xstrahl CIX3 cabinet irradiator, in vivo radiotherapy was delivered to the tumor only. Data An increased sensitivity to DDR agents when combined with radiotherapy was observed in vitro in both cell lines, compared to standalone treatments. A single dose of radiotherapy significantly reduced cell viability beyond the effects of radiotherapy or compound treatment alone. The induction of biomarkers by radiotherapy as monotherapy or in combination with DDR inhibitors was assessed. Changes in biomarker expression were consistent with those observed in the in vivo xenograft models. The administration of fractionated dosing regimens for radiotherapy was well-tolerated in vivo. Combination of radiotherapy with the DDR compounds led to tumor growth delay and enhanced survival outcomes. Conclusion In summary, in vitro assays and in vivo models have been established to investigate the synergistic effects of the combination of radiotherapy and DDR agents. Radiotherapy increased sensitivity of 2 human cancer cell lines to the DDR agents in vitro, and lead to tumor growth delay in vivo. These assays can be used as preclinical tools to identify novel compounds or mechanisms that can be successfully combined with radiotherapy.
Citation Format: Pablo Binder, Theoni Katopodi, Lyndsey Hanson, Charlotte R. Bell, Eimear Flanagan, Paul Farrington, Nick Moore, Emily Wright, Yin Xin Ho, Tobias Bunday, Stewart Brown, Amy Cantrell, Yael Mamane, Jon Greenall, Shannon Sharman, John Woolley, Lorraine M. Mooney, Jane Kendrew. Radiotherapy sensitizes preclinical models to DNA damage response agents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A004.