ESTRO 2024 - Abstract Book

S5391

Radiobiology - Tumour biology

ESTRO 2024

References:

1. Hooijmans, C.R., et al., SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol, 2014. 14: p. 43.

2. Macleod, M.R., et al., Pooling of animal experimental data reveals influence of study design and publication bias. Stroke, 2004. 35(5): p. 1203-8.

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Targeting DNA damage response to enhance radiation therapy lethality in CIC rearranged sarcomas

Camille Roukoz 1,2 , Virginie Perrin 2 , Mehdi Brahmi 2 , Helene Vanacker 2 , Franck Tirode 2 , Waisse Waissi 2,1

1 Centre Léon Berard, Radiotherapy, Lyon, France. 2 Cancer Research Center of Lyon, CRCL, Lyon, France

Purpose/Objective:

CIC-DUX4 sarcoma (CDS) is an aggressive round cell sarcoma, characterized by a specific oncogenic translocation, mainly CIC::DUX4. CDS has usually an aggressive clinical course with high rates of both local and metastatic relapse/progression. While there is no standard of care for the treatment of CDS, a multimodal therapy is usually preferred. (1) Radiotherapy (RT) damages the DNA cancer cells, by creating DNA double-strand breaks (DSBs) and many types of single-strand damages (SSDs) that may be repaired by different pathways of the DNA damage response (DDR) to promote genomic stability and cell survival. Hence, DDR proteins represent a compelling target to inhibit, in order to enhance the effects of RT. (2) ATR (Ataxia Telangiectasia Mutated and Rad-3 Related protein kinase) is a member of the PI3-kinase-like kinase family involved in DDR. ATR is activated by DSBs and replication stress caused by SSD. Once activated, a large network of proteins is phosphorylated in order to arrest the cell cycle and promote DNA repair, and/or programmed cell death pathways when the damage is too important. (3)

Cerelasertib (AZD6738) is a selective oral ATR inhibitor (ATRi), thus inducing DNA damage, and preventing DNA repair, leading to cell death.

We hypothesized that treating CDS cells with ATRi drugs can enhance the lethality of RT.

Material/Methods:

A comparative transcriptional analysis was performed between cell lines harbouring an oncogenic CIC::DUX4 fusion and their counterpart with siRNA based CIC::DUX4 knock down. Differential genes expression and enrichment