S2634
Radiobiology - Tumour radiobiology
ESTRO 2026
underlying its radioresistance remain unclear. This study aimed to elucidate the molecular basis of SCLC radioresistance and to explore potential therapeutic strategies to enhance radiosensitivity. Material/Methods: An orthotopic radioresistant SCLC model was established using SCLC organoids (Fig.A,B). Bulk RNA sequencing of radioresistant organoids and single-cell RNA sequencing of irradiated SCLC tumors were performed for transcriptomic profiling. The regulation of CCND1 expression by irradiation was validated by qPCR and immunofluorescence. CRISPR-Cas9– mediated CCND1 knockout was used to assess the impact of CCND1 loss on radiosensitivity. The antitumor efficacy and immune microenvironment alterations induced by combining a CDK4/6 inhibitor with radiotherapy were evaluated in both organoid and mouse SCLC models. Mechanistically, we analyzed the changes in neuroendocrine markers after irradiation and investigated the role of the YAP1–
CCND1 pathway in radioresistance through transcription factor prediction analyses. Results:
Transcriptomic analysis of radioresistant organoids and irradiated SCLC tumors revealed a significant upregulation of CCND1 in radioresistant SCLC (Fig.C,D). Radiotherapy induced CCND1 expression in both human and mouse SCLC organoids as well as in vivo tumors. CCND1 knockout markedly reduced the radioresistance of SCLC organoids (Fig.E). Combination therapy with a CDK4/6 inhibitor and radiotherapy significantly enhanced tumor cell killing, decreased recurrence and metastasis, and increased CD3 ⁺ T-cell infiltration(Fig.F-I). Mechanistically, irradiation suppressed ASCL1 while elevating YAP1, suggesting that subtype plasticity driven by the YAP1–CCND1 axis contributes to SCLC radioresistance (Fig.J).
Figure 2: Effect of Ro 90-7501, alone or with radiotherapy, on the cell survival of GM03652, MCF-7, MDA-MB-231, UM-UC-5 and T24, assessed by clonogenic assay (A) and by sphere formation assay (B). (*: p<0.05, **: p<0.01, ***: p<0.001). Conclusion: Ro 90-7501 demonstrated radiosensitizing effects in breast and bladder cancer cell lines at both the molecular and cellular levels, with minimal impact on normal fibroblasts. Keywords: Radiosensitivity, Ro 90-7501, DNA repair CDK4/6 Inhibitor Trilaciclib Combined with Radiotherapy Reverses Radioresistance and Improves the Immune Microenvironment in Small Cell Lung Cancer Yuanjun Wu, Ruoxi Zhang, Nanhao Yin, Jianxin Xue Division of Thoracic Tumor Multimodality Treatment, Sichuan University West China Hospital, Chengdu, China Purpose/Objective: Small cell lung cancer (SCLC) is a highly aggressive malignancy that initially responds well to radiotherapy but frequently relapses, and the mechanisms Poster Discussion 2896
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