ESTRO 2024 - Abstract Book

S5382

Radiobiology - Tumour biology

ESTRO 2024

foci assay and a standard clonogenic assay were performed to investigate the frequency of DSB and cell survival after irradiation, respectively.

Results:

YB-1 phosphorylated at S102 in the nucleus was detected only in cancer tissue and not in normal tissue. 47.2% of tumor tissues exhibited phosphorylation of YB-1 in the nucleus, which was positively correlated with KRAS mutation status (p=0.017). There was no significant correlation between phosphorylation of YB-1 in the cytoplasmic fraction and KRAS mutation status (p=0.391). Median survival was shorter in the subgroup of patients with nuclear phosphorylated YB-1. Although patients with phosphorylated YB-1 in the nucleus had markedly shorter cumulative survival (42 months vs. 28 months), no conclusion can be drawn due to the limited sample size. Data from an in vitro study showed that inhibition of YB-1 phosphorylation by fisetin was associated with increased DSB in non-irradiated cells and increased residual DSB after irradiation. Fisetin rendered CaCo2 cells radiosensitive regardless of KRAS mutation status. The radiosensitizing effect of fisetin was markedly stronger in KRAS G12V cells than in KRAS wt cells.

Conclusion:

Phosphorylated nuclear YB-1 may be a predictive marker of the efficacy of a combination of strategies targeting YB 1, such as the use of fisetin with radiotherapy for colorectal cancer tumors harboring a KRAS mutation.

Acknowledgments: Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG TO 685/2-3)

Keywords: Colorectal cancers, YB-1, KRAS

References:

1. Sechi, M., et al., Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models. Sci Rep, 2018. 8(1): p. 15726.

2. Toulany, M., et al., Impact of oncogenic K-RAS on YB-1 phosphorylation induced by ionizing radiation. Breast Cancer Res, 2011. 13(2): p. R28.

3. Lettau, K., D. Zips, and M. Toulany, Simultaneous Targeting of RSK and AKT Efficiently Inhibits YB-1-Mediated Repair of Ionizing Radiation-Induced DNA Double-Strand Breaks in Breast Cancer Cells. Int J Radiat Oncol Biol Phys, 2021. 109(2): p. 567-580.

4. Rossner, F., et al., Uncoupling of EGFR-RAS signaling and nuclear localization of YBX1 in colorectal cancer. Oncogenesis, 2016. 5: p. e187.

5. Gunn, A. and J.M. Stark, I-SceI-based assays to examine distinct repair outcomes of mammalian chromosomal double strand breaks. Methods Mol Biol, 2012. 920: p. 379-91.