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Translational Therapeutics

Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours

British Journal of Cancer volume 125, pages 1511–1522 (2021)Cite this article

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Abstract

Background

Despite the effectiveness of tyrosine kinase inhibitors (TKI), gastrointestinal stromal tumours (GIST) develop after the withdrawal of TKI. Based on previous studies, a subpopulation of drug-tolerant cells called “persister cells” may be responsible for the recurrence and have thus, gained attention as a novel target in cancer therapy.

Methods

The metabolic changes were investigated in imatinib-derived persister GIST cells. We investigated the efficacy and the mechanism of GPX4 inhibitor, which is known as a major inducer of “ferroptosis”. We also evaluated the effects of RSL3 to the gefitinib-derived persister lung cancer cells.

Results

We demonstrated a downregulation of glucose metabolism, subsequent decrease in the glutathione level and sensitivity to glutathione peroxidase 4 (GPX4) inhibitor, RSL3 in persister cells. As the cell death induced by RSL3 was found to be “iron-dependent” and “caspase-independent”, loss of GPX4 function could have possibly induced selective persister cell ferroptotic death. In the xenograft model, we confirmed the inhibition of tumour regrowth after discontinuation of imatinib treatment. Moreover, RSL3 prevented the growth of gefitinib-derived persister lung cancer cells.

Conclusions

RSL3 combined with TKI may be a promising therapy for both GIST and epidermal growth factor receptor-mutated lung cancer.

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Fig. 1: Characterisation of imatinib-derived gastrointestinal stromal tumour (GIST) persister cells.
Fig. 2: GSH-related metabolic change in persister cells.
Fig. 3: Glucose-related metabolism was altered in persister cells.
Fig. 4: Persister cells are vulnerable to glutathione peroxidase 4 (GPX4) inhibition.
Fig. 5: Subcutaneous tumour model established to analyze the effect of RSL3.
Fig. 6: The characteristics of persister cells and the effect of RSL3 (glutathion peroxidase 4 [GPX4] inhibitor) on persister cells in other cell lines (epidermal growth factor receptor (EGFR)-mutant lung cancer cell line PC9 and mutational imatinib-resistant gastrointestinal stromal tumour [GIST] cell line GIST-R8).

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Data availability

The datasets generated/analyzed during the current study are not publicly available as they contain private information pertaining to the research participants but are available on request from the corresponding author (TT).

References

  1. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.

    Article  CAS  Google Scholar 

  2. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10.

    Article  CAS  Google Scholar 

  3. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80.

    Article  CAS  Google Scholar 

  4. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–5.

    Article  CAS  Google Scholar 

  5. Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)-update of the NCCN clinical practice guidelines. J Natl Compr Cancer Netw. 2007;5:S1–29.

    Article  Google Scholar 

  6. Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009;15:7510–8.

    Article  CAS  Google Scholar 

  7. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9.

    Article  CAS  Google Scholar 

  8. Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004;40:689–95.

    Article  CAS  Google Scholar 

  9. Ramirez M, Rajaram S, Steininger RJ, Osipchuk D, Roth MA, Morinishi LS, et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat Commun. 2016;7:10690.

    Article  CAS  Google Scholar 

  10. Stockwell BR, Friedmann AJP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.

    Article  CAS  Google Scholar 

  11. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  Google Scholar 

  12. Conrad M, Angeli JP, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016;15:348–66.

    Article  CAS  Google Scholar 

  13. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76.

    Article  CAS  Google Scholar 

  14. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.

    Article  CAS  Google Scholar 

  15. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.

    Article  CAS  Google Scholar 

  16. Saito Y, Takahashi T, Obata Y, Nishida T, Ohkubo S, Nakagawa F, et al. TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours. Br J Cancer. 2020;122:658–67.

    Article  CAS  Google Scholar 

  17. Takahashi T, Elzawahry A, Mimaki S, Furukawa E, Nakatsuka R, Nakamura H, et al. Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2017;56:303–13.

    Article  CAS  Google Scholar 

  18. Sugase T, Takahashi T, Serada S, Fujimoto M, Hiramatsu K, Ohkawara T, et al. SOCS1 gene therapy improves radiosensitivity and enhances irradiation-induced DNA damage in esophageal squamous cell carcinoma. Cancer Res. 2017;77:6975–86.

    Article  CAS  Google Scholar 

  19. Dawson CC, Intapa C, Jabra-Rizk MA. “Persisters”: survival at the cellular level. PLoS Pathog. 2011;7:e1002121.

    Article  CAS  Google Scholar 

  20. Lantermann AB, Chen D, McCutcheon K, Hoffman G, Frias E, Ruddy D, et al. Inhibition of casein kinase 1 alpha prevents acquired drug resistance to erlotinib in EGFR-mutant non-small cell lung cancer. Cancer Res. 2015;75:4937–48.

    Article  CAS  Google Scholar 

  21. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.

    Article  CAS  Google Scholar 

  22. Oxnard GR. The cellular origins of drug resistance in cancer. Nat Med. 2016;22:232–4.

    Article  CAS  Google Scholar 

  23. Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22:262–9.

    Article  CAS  Google Scholar 

  24. Patrikidou A, Chabaud S, Ray-Coquard I, Bui BN, Adenis A, Rios M, et al. Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial. Ann Oncol. 2013;24:1087–93.

    Article  CAS  Google Scholar 

  25. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172:409–22.e421.

    Article  CAS  Google Scholar 

  26. Proneth B, Conrad M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. 2019;26:14–24.

    Article  CAS  Google Scholar 

  27. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014;39:347–54.

    Article  CAS  Google Scholar 

  28. Shimada K, Hayano M, Pagano NC, Stockwell BR. Cell-line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem Biol. 2016;23:225–35.

    Article  CAS  Google Scholar 

  29. Bose S, Le A. Glucose metabolism in cancer. Adv Exp Med Biol. 2018;1063:3–12.

    Article  CAS  Google Scholar 

  30. Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol. 2017;24:1161–80.

    Article  CAS  Google Scholar 

  31. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.

    Article  CAS  Google Scholar 

  32. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 2001;276:9519–25.

    Article  CAS  Google Scholar 

  33. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008;8:705–13.

    Article  CAS  Google Scholar 

  34. Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK, et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 2001;12:363–9.

    PubMed  CAS  Google Scholar 

  35. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993–8.

    Article  CAS  Google Scholar 

  36. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.

    Article  CAS  Google Scholar 

  37. Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D, et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci USA. 2010;107:14333–8.

    Article  Google Scholar 

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Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This work was not supported by any organizations besides Osaka University.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan

    Tomo Ishida, Tsuyoshi Takahashi, Yukinori Kurokawa, Ryugo Teranishi, Takuro Saito, Kotaro Yamashita, Koji Tanaka, Kazuyoshi Yamamoto, Tomoki Makino, Makoto Yamasaki, Kiyokazu Nakajima, Hidetoshi Eguchi & Yuichiro Doki

  2. Department of Surgery, Japan Community Health Care Organization Osaka Hospital, 4-2-78, Fukushima, Fukushima-ku, Osaka, Japan

    Toshirou Nishida

  3. Department of Surgical Pathology, Hyogo College of Medicine, 1-1, Mukogawacho, Nishinomiya, Hyogo, Japan

    Seiichi Hirota

  4. Center for Intractable Disease, Kochi University, Nankoku, Japan

    Satoshi Serada, Minoru Fujimoto & Tetsuji Naka

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  1. Tomo Ishida
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Contributions

TI wrote the initial draft of the manuscript. TT contributed to the analysis and interpretation of data and assisted in the preparation of the manuscript. All coauthors contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to accuracy or integrity of any part of the work are appropriately investigated and resolved. Conception and design: TI and TT. Methodology development: TI and TT. Data acquisition: TI, RT and TT. Data analysis and interpretation: TI, TT, TN, SH, SS, MF, TN, YK, TS, KY, KT, KY, TM, MY, KN, HE and YD. Manuscript writing, review and/or revision: TI, TT, HE and YD. Study supervision: TT.

Corresponding author

Correspondence to Tsuyoshi Takahashi.

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Ethics approval and consent to participate

The Human Ethics Review Committee of Osaka University Graduate School of Medicine approved the protocol for this retrospective study, and each participant provided written informed consent for study participation (ethical approval number: 27-061-002). All procedures were conducted in accordance with the principles underlying the Declaration of Helsinki and its later amendments.

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Consent for publication has been obtained from the person whose data were on the paper.

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The authors declare no competing interests.

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Ishida, T., Takahashi, T., Kurokawa, Y. et al. Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours. Br J Cancer 125, 1511–1522 (2021). https://doi.org/10.1038/s41416-021-01566-9

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