S2635
Radiobiology - Tumour radiobiology
ESTRO 2026
Digital Poster 3558 Multi-Model Transcriptomic Profiling Identifies Core Gene Networks of Prostate Cancer Radioresistance Taha Q Lodhi 1,2 , Conrado G Quiles 1 , Amen Shamim 1 , Vanesa Biolatti 1 , Stephen Lyons 1 , Kimberley Reeves 1 , Roylin Pereira 1 , Hugo Seaborne 1 , Hannah Nolan 1 , Thi Ngoc Anh Pham 1 , Laura Forker 2 , Anthony Adamson 1 , Robert Bristow 1 , David Wedge 1 , Peter Hoskin 1,3 , Ananya Choudhury 1,2 1 Divison of Cancer Sciences, University of Manchester, Manchester, United Kingdom. 2 Clinical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom. 3 Clinical Oncology, Mount Vernon Cancer Centre, London, United Kingdom Purpose/Objective: Radiotherapy is central to prostate cancer (PCa) management, yet treatment failure can occur in one- third of patients1. Tumour cell radioresistance is a probable factor underpinning failure, but inherent radioresistance pathways are unclear due to a lack of isogenic cell models. This study modelled intrinsic PCa radioresistance based on conserved transcriptomic changes to identify candidate biomarkers of poor treatment response. Material/Methods: Radioresistant sublines were generated by exposing metastatic DU145 and isogenic primary TERT- immortalised prostate epithelial models (TERT-PrEC) to 60 Gy in 20 fractions in vitro. Clonogenic survival assays confirmed acquired radioresistance. The isogenic TERT-PrEC panel comprised CTRL, MYC overexpression, and TP53 knockout with MYC overexpression (P53MYC), representing key oncogenic drivers of PCa. RNA sequencing (Illumina NovaSeq 6000) was performed on resistant and matched control lines. Differential expression was assessed using DESeq2 (v1.40.2)2 with |log ₂ FC| ≥ 1, padj < 0.05. Weighted gene co-expression network analysis (WGCNA) identified co-regulated gene modules associated with radioresistance. Functional enrichment and network clustering (Gene Ontology, Reactome, STRING) were used to define resistance- associated pathways and biological processes. Results: Seven post-irradiation in vitro radioresistant models were established: DU145-R1, -R2, -R3 and TERT-PrEC CTRL-R2, CTRL-R3, MYC-R1, P53MYC-R1. Clonogenic assays confirmed stable resistance compared to matched controls (DU145, p < 0.001, n = 6; TERT-PrEC, p < 0.01–0.001, n = 6). In DU145 models, radioresistance was associated with gene networks involved in axonogenesis (R1), mitotic control (R2), and extracellular matrix (ECM) organisation (R3), while TERT-PrEC models showed activation of oxidative
Conclusion: This study identifies activation of the YAP1–CCND1 pathway as a key driver of radioresistance in small cell lung cancer. Targeting the CCND1–CDK4/6 axis effectively reverses radioresistance, enhances antitumor efficacy, and remodels the immune microenvironment. These findings highlight the potential of combining CDK4/6 inhibition with radiotherapy—and possibly immunotherapy—as a promising strategy to overcome the clinical challenge of “initially radiosensitive but rapidly relapsing” SCLC. Keywords: Radiotherapy resistance, Lung cancer, CCND1
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