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Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids

Abstract

Despite recent advances in sequencing technology and large-scale drug screenings employing hundreds of cell lines, the predictive accuracy of mutation-based biomarkers is still insufficient as a guide for cancer therapy. Therefore, novel types of diagnostic methods using alternative biomarkers would be highly desirable. We have hypothesized that sensitivity-specific changes in the phosphorylation of signaling molecules could be useful in this respect. Here, with the aim of developing a method for predicting the response of cancers to cisplatin using a combination of specific biomarker(s) and patient-derived tumor organoids (PDOs), we found that cisplatin-sensitive cell lines or PDOs showed enhanced phosphorylation of c-Jun (p-c-Jun) within 24 h after cisplatin treatment. We also compared the responses of 6 PDOs to cisplatin with the therapeutic effect of neoadjuvant chemotherapy (docetaxel/cisplatin/5-fluorouracil) in 6 matched patients. Mechanistically, the c-Jun induction was partly related to TNF signaling induced by cisplatin. Our data suggest that enhanced phosphorylation of c-Jun in response to cisplatin treatment could be a predictive biomarker for the efficacy of cisplatin in selected cancer patients.

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Fig. 1: Enhanced phosphorylation of p38 and c-Jun after cisplatin treatment is related to cisplatin sensitivity in GC cell lines.
Fig. 2: Histopathological characterization of PDOs.
Fig. 3: Enhanced phosphorylation of c-Jun after cisplatin treatment is related to cisplatin sensitivity in PDOs.
Fig. 4: Induced TNFα is partly related to the enhanced phosphorylation of c-Jun after cisplatin treatment.
Fig. 5: Contribution of JNK/c-Jun activation to cisplatin-induced apoptosis.

Data availability

The data that support the findings of this study are available from the corresponding authors, upon reasonable request.

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Acknowledgements

We would like to thank Ms. Mami Kimoto for technical assistance. We are also grateful to Prof. Hans Clevers, Dr. Georg A Busslinger, Dr. Else Driehuis and Ms. Stieneke van den Brink for critical advice on organoid experiments. This work was supported by Oita University President’s Strategic Discretionary Fund (2020 and 2021), by JSPS KAKENHI Grant Numbers JP21H02703 and JP18H02631, by Takeda Science Foundation (2020) and by Japan AMED Translational Research Network Project Seeds A (A232).

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Conceptualization Y.T., Y.H. and M.M.; Formal analysis and investigation Y.T., S.K., S.F., S.Y. and F.M.; Writing—original draft preparation Y.T., Y.H., N.H. and M.M.; Writing—review and editing T.S., K.o.S., S.F., K.Y., C.N., K.K., T.F., K.M.i., Y.U., T.E., T.U,. M.T,. T.D., K.u.S., S.H,. K.M.u. and M.I.; Funding acquisition Y.T.; Resources T.S., K.o.S., Y.H., S.F., K.Y., K.M.i., Y.U., T.E., T.H,. S.H., K.M.u. and M.I.; Supervision: K.M.u., M.I., N.H. and M.M. All authors have approved the final version of the paper.

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Correspondence to Yoshiyuki Tsukamoto.

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This study was approved by the ethics committee of Oita University Faculty of Medicine (approval No. 1495 and 1496).

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Tsukamoto, Y., Kurogi, S., Shibata, T. et al. Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00827-2

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