S2642
Radiobiology - Tumour radiobiology
ESTRO 2026
radiosensitisation using baseline tumour molecular profiles. This may be a consequence of temporal evolution in cytoprotective mechanisms in response to fractionated radiotherapy. To test this hypothesis, we characterised genomic and transcriptomic evolution in response to a clinically relevant radiotherapy dose- fractionation schedule in patient-derived organoids resembling oesophageal adenocarcinoma (OAC); a malignancy of unmet need that responds inadequately to radiotherapy in as many as 80% of patients1. Material/Methods: A single PDO was derived from a surgical resection specimen obtained from a patient with OAC who had previously received neoadjuvant chemoradiotherapy. This PDO was exposed on three separate occasions to 30Gy in 15 fractions x-ray irradiation delivered over three weeks. Molecular characteristics of the PDO and its parent tissue were assessed at baseline using 30X/50X whole genome sequencing (WGS), RNA sequencing and methylation profiling using a Twist 123Mb human methylome panel, with these repeated at 10Gy dose intervals in the irradiated PDOs. Relative radiation sensitivity of treatment-naïve and the three 30Gy irradiated PDOs (30Gy A, B, C) was assessed by single fraction exposure of PDOs one day after plating to 0-8Gy and subsequent calculation of relative organoid formation efficiency (OFE). Results: Relative OFE was higher in two of the three 30Gy irradiated PDOs than in a passage-matched treatment- naïve organoid (Figure 1A). WGS revealed a dose- dependent increase in insertion-deletion and single nucleotide variant mutation burden (Figure 1B). Analysis of mutational signatures revealed a similar dose-dependent enrichment of microhomology deletions (Figure 1C), suggesting a role for alternative end joining and polymerase theta in mediating OAC response to fractionated radiotherapy.
exposure. DNA damage response and apoptosis markers were evaluated by immunohistochemistry and Western blot. Quantitative comparisons leveraging TCGA-HNSC data validated differential AXL expression patterns in tumor versus normal tissues and relative to TP53 mutation status. Results: AXL expression was elevated in HNSCC tumor tissues and TP53-mutant samples compared to normal or TP53–wildtype counterparts. Cell lines displayed heterogeneous AXL mRNA and protein levels, with AXL protein abundance inversely correlated with p53 protein. Pharmacological inhibition of AXL reduced clonogenic survival and cell viability. Distinct intracellular localization of AXL was observed, altered by irradiation exposure. Conclusion: Elevated AXL expression is associated with poorer survival and local-regional control after radiotherapy and radiochemotherapy. AXL inhibition sensitizes TP53-mutant cells to radiotherapy by inducing replication stress and synthetic lethality, while in TP53–wildtype cells, combined therapy triggers senescence that may synergize with xenolytic agents. These findings support a personalized approach, using AXL and TP53 status to guide combination treatment strategies in HNSCC. References: Busch CJ, Hagel C, Becker B, Oetting A, Möckelmann N, Droste C, Möller-Koop C, Witt M, Blaurock M, Loges S, Rothkamm K, Betz C, Münscher A, Clauditz TS, Rieckmann T. Tissue Microarray Analyses Suggest Axl as a Predictive Biomarker in HPV-Negative Head and Neck Cancer. Cancers (Basel). 2022 Apr 5;14(7):1829. doi: 10.3390/cancers14071829. PMID: 35406601; PMCID: PMC8997923. Keywords: TP53, AXL, DNA-damage response Dopamine signalling and polymerase theta are potential mediators of radiation response in oesophageal adenocarcinoma Kayli Bolton 1,2 , Daniel Jacobson 1,2 , Gunjan Katyal 1,3 , Joanna Kucharczak 1,2 , Victoria Askinyte 2 , Hannah Coles 2 , Ginny Devonshire 2 , Rebecca C Fitzgerald 2 , Christopher M Jones 1,2 1 CRUK RadNet Cambridge, University of Cambridge, Cambridge, United Kingdom. 2 Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom. 3 CRUK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom Purpose/Objective: There is a longstanding failure across multiple malignancies to identify effective targets for Digital Poster 5042
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