Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Molecular Diagnostics

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

British Journal of Cancer volume 125, pages 65–77 (2021)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J. Cancer 136, E359–E386 (2015).

    Article  CAS  Google Scholar 

  2. Davidson, M., Okines, A. F. & Starling, N. Current and future therapies for advanced gastric cancer. Clin. Colorectal Cancer 14, 239–250 (2015).

    Article  Google Scholar 

  3. Takahari, D., Chin, K., Ishizuka, N., Takashima, A., Minashi, K., Kadowaki, S. et al. Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naive, HER2-positive advanced gastric cancer. Gastric Cancer 22, 1238–1246 (2019).

    Article  CAS  Google Scholar 

  4. Yamada, Y., Higuchi, K., Nishikawa, K., Gotoh, M., Fuse, N., Sugimoto, N. et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer. Ann. Oncol. 26, 141–148 (2015).

    Article  CAS  Google Scholar 

  5. Murai, J. & Targeting, D. N. A. repair and replication stress in the treatment of ovarian cancer. Int J. Clin. Oncol. 22, 619–628 (2017).

    Article  CAS  Google Scholar 

  6. Murai, J., Thomas, A., Miettinen, M. & Pommier, Y. Schlafen 11 (SLFN11), a restriction factor for replicative stress induced by DNA-targeting anti-cancer therapies. Pharm. Ther. 201, 94–102 (2019).

    Article  CAS  Google Scholar 

  7. Li, M., Kao, E., Malone, D., Gao, X., Wang, J. Y. J. & David, M. DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs. Nat. Struct. Mol. Biol. 25, 1047–1058 (2018).

    Article  Google Scholar 

  8. Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S. et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

    Article  CAS  Google Scholar 

  9. Zoppoli, G., Regairaz, M., Leo, E., Reinhold, W. C., Varma, S., Ballestrero, A. et al. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc. Natl Acad. Sci. USA 109, 15030–15035 (2012).

    Article  CAS  Google Scholar 

  10. Tang, S. W., Thomas, A., Murai, J., Trepel, J. B., Bates, S. E., Rajapakse, V. N. et al. Overcoming resistance to DNA-targeted agents by epigenetic activation of Schlafen 11 (SLFN11) expression with class I histone deacetylase inhibitors. Clin. Cancer Res. 24, 1944–1953 (2018).

    Article  CAS  Google Scholar 

  11. Rathkey, D., Khanal, M., Murai, J., Zhang, J., Sengupta, M., Jiang, Q. et al. Sensitivity of mesothelioma cells to PARP inhibitors is not dependent on BAP1 but Is enhanced by temozolomide in cells with high-Schlafen 11 and low-O6-methylguanine-DNA methyltransferase expression. J. Thorac. Oncol. 15, 843–859 (2020).

    Article  CAS  Google Scholar 

  12. Murai, J., Feng, Y., Yu, G. K., Ru, Y., Tang, S. W., Shen, Y. et al. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 7, 76534–76550 (2016).

    Article  Google Scholar 

  13. Marzi, L., Agama, K., Murai, J., Difilippantonio, S., James, A., Peer, C. J. et al. Novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors. Mol. Cancer Ther. 17, 1694–1704 (2018).

    Article  CAS  Google Scholar 

  14. Lok, B. H., Gardner, E. E., Schneeberger, V. E., Ni, A., Desmeules, P., Rekhtman, N. et al. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin. Cancer Res 23, 523–535 (2017).

    Article  CAS  Google Scholar 

  15. Iwasaki, J., Komori, T., Nakagawa, F., Nagase, H., Uchida, J., Matsuo, K. et al. Schlafen11 expression is associated with the antitumor activity of trabectedin in human sarcoma cell lines. Anticancer Res. 39, 3553–3563 (2019).

    Article  CAS  Google Scholar 

  16. Gardner, E. E., Lok, B. H., Schneeberger, V. E., Desmeules, P., Miles, L. A., Arnold, P. K. et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2-SLFN11 Axis. Cancer Cell 31, 286–299 (2017).

    Article  CAS  Google Scholar 

  17. Coussy, F., El-Botty, R., Chateau-Joubert, S., Dahmani, A., Montaudon, E., Leboucher, S. et al. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci. Transl. Med. 12, aax2625 (2020).

  18. Conteduca, V., Ku, S. Y., Puca, L., Slade, M., Fernandez, L., Hess, J. et al. SLFN11 expression in advanced prostate cancer and response to platinum-based chemotherapy. Mol. Cancer Ther. 19, 1157–1164 (2020).

    Article  CAS  Google Scholar 

  19. Pietanza, M. C., Waqar, S. N., Krug, L. M., Dowlati, A., Hann, C. L., Chiappori, A. et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J. Clin. Oncol. 36, 2386–2394 (2018).

    Article  CAS  Google Scholar 

  20. Winkler, C., Armenia, J., Jones, G. N., Tobalina, L., Sale, M. J., Petreus, T. et al. SLFN11 informs on standard of care and novel treatments in a wide range of cancer models. Br. J. Cancer https://doi.org/10.1038/s41416-020-01199-4 (2020).

  21. Kagami, T., Yamade, M., Suzuki, T., Uotani, T., Tani, S., Hamaya, Y. et al. The first evidence for SLFN11 expression as an independent prognostic factor for patients with esophageal cancer after chemoradiotherapy. BMC Cancer 20, 1123 (2020).

    Article  CAS  Google Scholar 

  22. Murai, J., Tang, S. W., Leo, E., Baechler, S. A., Redon, C. E., Zhang, H. et al. SLFN11 Blocks stressed replication forks independently of ATR. Mol. Cell 69, 371–384.e376 (2018).

    Article  CAS  Google Scholar 

  23. Murai, J., Zhang, H., Pongor, L., Tang, S. W., Jo, U., Moribe, F. et al. Chromatin remodeling and immediate early gene activation by SLFN11 in response to replication stress. Cell Rep. 30, 4137–4151 e4136 (2020).

    Article  CAS  Google Scholar 

  24. Nogales, V., Reinhold, W. C., Varma, S., Martinez-Cardus, A., Moutinho, C., Moran, S. et al. Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs. Oncotarget 7, 3084–3097 (2016).

    Article  Google Scholar 

  25. Peng, Y., Wang, L., Wu, L., Zhang, L., Nie, G. & Guo, M. Methylation of SLFN11 promotes gastric cancer growth and increases gastric cancer cell resistance to cisplatin. J. Cancer 10, 6124–6134 (2019).

    Article  CAS  Google Scholar 

  26. Takashima, T., Sakamoto, N., Murai, J., Taniyama, D., Honma, R., Ukai, S. et al. Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq. Virchows Arch https://doi.org/10.1007/s00428-020-02840-6 (2020).

  27. Namikawa, T. & Hanazaki, K. Mucin phenotype of gastric cancer and clinicopathology of gastric-type differentiated adenocarcinoma. World J. Gastroenterol. 16, 4634–4639 (2010).

    Article  Google Scholar 

  28. Ishikawa, A., Sakamoto, N., Honma, R., Taniyama, D., Fukada, K., Hattori, T. et al. Annexin A10 is involved in the induction of pancreatic duodenal homeobox1 in gastric cancer tissue, cells and organoids. Oncol. Rep. 43, 581–590 (2020).

    CAS  PubMed  Google Scholar 

  29. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

  30. Yoo, C. H., Noh, S. H., Shin, D. W., Choi, S. H. & Min, J. S. Recurrence following curative resection for gastric carcinoma. Br. J. Surg. 87, 236–242 (2000).

    Article  CAS  Google Scholar 

  31. D'Angelica, M., Gonen, M., Brennan, M. F., Turnbull, A. D., Bains, M. & Karpeh, M. S. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann. Surg. 240, 808–816 (2004).

    Article  Google Scholar 

  32. Seidlitz, T., Merker, S. R., Rothe, A., Zakrzewski, F., von Neubeck, C., Grutzmann, K. et al. Human gastric cancer modelling using organoids. Gut 68, 207–217 (2019).

    Article  CAS  Google Scholar 

  33. Narasimhan, V., Wright, J. A., Churchill, M., Wang, T., Rosati, R., Lannagan, T. R. M. et al. Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases to direct personalized therapy. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-20-0073 (2020).

  34. Yao, Y., Xu, X., Yang, L., Zhu, J., Wan, J., Shen, L. et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 26, 17–26 e16 (2020).

    Article  CAS  Google Scholar 

  35. Dombret, H., Seymour, J. F., Butrym, A., Wierzbowska, A., Selleslag, D., Jang, J. H. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126, 291–299 (2015).

    Article  CAS  Google Scholar 

  36. Fenaux, P., Mufti, G. J., Hellstrom-Lindberg, E., Santini, V., Finelli, C., Giagounidis, A. et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 10, 223–232 (2009).

    Article  CAS  Google Scholar 

  37. Ryan, Q. C., Headlee, D., Acharya, M., Sparreboom, A., Trepel, J. B., Ye, J. et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J. Clin. Oncol. 23, 3912–3922 (2005).

    Article  CAS  Google Scholar 

  38. Ivanova, T., Zouridis, H., Wu, Y., Cheng, L. L., Tan, I. B., Gopalakrishnan, V. et al. Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut 62, 22–33 (2013).

    Article  CAS  Google Scholar 

  39. Kimura, A., Ogata, K., Altan, B., Yokobori, T., Ide, M., Mochiki, E. et al. Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer. Oncotarget 7, 18415–18423 (2016).

    Article  Google Scholar 

  40. Ye, Y., Li, J., Jiang, D., Li, J., Xiao, C., Li, Y. et al. FGFR4 Gly388Arg polymorphism affects the progression of gastric cancer by activating STAT3 pathway to induce epithelial to mesenchymal transition. Cancer Res. Treat. https://doi.org/10.4143/crt.2020.138 (2020).

  41. Ye, Y., Li, X., Yang, J., Miao, S., Wang, S., Chen, Y. et al. MDM2 is a useful prognostic biomarker for resectable gastric cancer. Cancer Sci. 104, 590–598 (2013).

    Article  CAS  Google Scholar 

  42. Fan, Y., Ying, H., Wu, X., Chen, H., Hu, Y., Zhang, H. et al. The mutational pattern of homologous recombination (HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer. Cancer Biol. Med. 17, 1002–1013 (2020).

    Article  CAS  Google Scholar 

  43. Mu, Y., Lou, J., Srivastava, M., Zhao, B., Feng, X. H., Liu, T. et al. SLFN11 inhibits checkpoint maintenance and homologous recombination repair. EMBO Rep. 17, 94–109 (2016).

    Article  CAS  Google Scholar 

  44. Murai, J. & Pommier, Y. PARP trapping beyond homologous recombination and platinum sensitivity in cancers. Annu Rev. Cancer Biol. 3, 131–150 (2019).

    Article  Google Scholar 

Download references

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.

Author information

Author notes

  1. These authors contributed equally: Tsuyoshi Takashima, Daiki Taniyama

Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Tsuyoshi Takashima, Daiki Taniyama, Naoya Sakamoto, Maika Yasumoto, Ryuichi Asai, Takuya Hattori, Ririno Honma, Pham Quoc Thang, Shoichi Ukai, Ryota Maruyama, Kenji Harada & Wataru Yasui

  2. Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan

    Tsuyoshi Takashima & Eiichi Morii

  3. Institute for Clinical Research, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan

    Kazuya Kuraoka

  4. Department of Diagnostic Pathology, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan

    Kazuya Kuraoka

  5. Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Kazuaki Tanabe & Hideki Ohdan

  6. Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA

    Atsuo T. Sasaki

  7. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan

    Atsuo T. Sasaki & Junko Murai

Authors
  1. Tsuyoshi Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daiki Taniyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoya Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maika Yasumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryuichi Asai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takuya Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ririno Honma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pham Quoc Thang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shoichi Ukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ryota Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kenji Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kazuya Kuraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazuaki Tanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Atsuo T. Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hideki Ohdan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eiichi Morii
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Junko Murai
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Wataru Yasui
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Consent to publish

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takashima, T., Taniyama, D., Sakamoto, N. et al. Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers. Br J Cancer 125, 65–77 (2021). https://doi.org/10.1038/s41416-021-01364-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01364-3

This article is cited by

Search

Advanced search

Quick links