ESTRO 2024 - Abstract Book

S5392

Radiobiology - Tumour biology

ESTRO 2024

analyses were performed. Three cell lines (IB120, RSP7-C1 and TE-441.T) were treated in monolayer, with increasing concentration of ATRi (AZD 6738 : 10nM-5µM) and/or RT (2Gy-4Gy). Then, organoids radiosensitisation was assessed with increasing concentration of AZD 6738 (100nM-2µM) and/or irradiation (2Gy-4Gy).

Results:

Replicative stress terms were significantly enriched in CDS as compared to other sarcoma subtypes. When knocking down CIC::DUX4, we showed a significant decrease in genes involved in replication stress (Replication Stress Score = 40.2 ± 0.8 vs 30.9 ± 1.4 ; p<0.05) (Figure 1). AZD6738 had a cytotoxic effect on all 3 CDS cell lines as compared to non CDS cell line (A549). Indeed, the AZD6738 IC50 was of 490 nM (IC95 : 410-590 nM), 510 nM (IC95 : 480-540 nM) and 980 nM (IC95 : 820-1200 nM) for RSP7-C1, TE-441.T and IB120 respectively. These results were similar in both monolayer and organoid models. The radiosensitivity effect of AZD6738 was then tested, at 2 and 4 Gy and showed a radiosensitisation effect at non-cytotoxic concentrations of AZD6738. For example, at day 10 post-irradiation, IB120 cells pretreated with 500nM of ATRi had a 45% reduction in organoid volumes compared to irradiation alone (Figure

2). Figure 1: Box plot showing a decrease in replication stress score after CIC::DUX4 inhibition in both IB120 and RSP7.C1 lines