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Molecular Diagnostics

Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers

Abstract

Background

Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC.

Methods

We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids.

Results

GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs.

Conclusions

This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.

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Fig. 1: High expression of SLFN11 is a favourable prognostic marker for gastric cancer (GC) treated with platinum-based chemotherapy.
Fig. 2: SLFN11 expression is a major determinant of sensitivity to DNA-damaging agents in GC cell lines.
Fig. 3: Epigenetic activation of SLFN11 further sensitises a GC cell line MKN-74 to DNA-damaging agents.
Fig. 4: GC cells acquire resistance to oxaliplatin while inactivating SLFN11.
Fig. 5: Low-SLFN11 organoids acquire sensitivity to DNA-damaging agents in combination with epigenetic modifying drugs.
Fig. 6: GC organoids acquire resistance to oxaliplatin while suppressing SLFN11 expression.

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Acknowledgements

The authors thank Mr. Shinichi Norimura (Technical Center, Hiroshima University) for his excellent technical assistance. We appreciate Dr. Eric Smith at the University of Cincinnati for the professional editing. We also thank the Analysis Center of Life Science of Hiroshima University for the use of their facilities.

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Authors

Contributions

T.T., N.S. and J.M. designed the study. T.T., D.T., N.S., R.A., R.H., U.K., K.K., K.T. and H.O. collected and analysed the patient clinical data. T.T., D.T, M.Y., R.A., T.H., R.H., P.Q.T., S.U., R.M. and K.H. performed the experiments and collected and analysed the data. K.K., H.O., AT.S., E.M. and W.Y. interpreted and analysed the results. T.T., D.T., N.S., AT.S. and J.M. drafted and edited the paper. All of the authors read and approved the final paper.

Corresponding authors

Correspondence to Naoya Sakamoto or Junko Murai.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Kure Medical Center and Chugoku Cancer Center, Kure, Japan (No. 2019-36), Human Genome Research of Hiroshima University, Hiroshima (E 597 01) and conformed to the ethical guidelines of the Declaration of Helsinki. All patients provided written informed consent to participate in this study.

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Not applicable.

Data availability

All the data supporting the findings of this study are available within the Supplementary Information files and from the corresponding authors on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by Grants-in-Aid for Scientific Research (JP15H04713 and JP16K08691 to W.Y., JP16H06999 to N.S. and JP19H03505 to J.M.), Challenging Exploratory Research (26670175, JP16K15247 to W.Y.) from the Japan Society for the Promotion of Science, the National Institute of Health (NIH) (R01NS089815 to A.T.S.) and a research grant from The Uehara Memorial Foundation (to J.M.). This work was supported in part by research funds from the Yamagata prefectural government and the City of Tsuruoka.

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Takashima, T., Taniyama, D., Sakamoto, N. et al. Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01364-3

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