Skip to main content

Advertisement

SpringerLink
Log in

FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1

  • Original Article
  • Published:
Gastric Cancer Aims and scope Submit manuscript

Abstract

Background

Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent.

Methods

The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs.

Results

The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo.

Conclusions

FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All presented data are available from the corresponding author upon reasonable request.

References

  1. Soreide K, Sandvik OM, Soreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 2016;40:39–46.

    Article  PubMed  Google Scholar 

  2. Serrano C, George S. Gastrointestinal stromal tumor: challenges and opportunities for a new decade. Clin Cancer Res. 2020;26:5078–85.

    Article  CAS  PubMed  Google Scholar 

  3. von Mehren M, Kane JM, Bui MM, Choy E, Connelly M, Dry S. NCCN guidelines insights: soft tissue sarcoma, version 1.2021. J Natl Compr Canc Netw. 2020;18:1604–12.

    Article  Google Scholar 

  4. Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2022;33:20–33.

    Article  CAS  PubMed  Google Scholar 

  5. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–72.

  7. Patrikidou A, Chabaud S, Ray-Coquard I, Bui BN, Adenis A, Rios M. 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  PubMed  Google Scholar 

  8. Wardelmann E, Thomas N, Merkelbach-Bruse S, Pauls K, Speidel N, Buttner R. Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol. 2005;6:249–51.

    Article  CAS  PubMed  Google Scholar 

  9. Alkhuziem M, Burgoyne AM, Fanta PT, Tang CM, Sicklick JK. The call of “the wild”-type GIST: it’s time for domestication. J Natl Compr Canc Netw. 2017;15:551–4.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11:865–78.

    Article  CAS  PubMed  Google Scholar 

  11. Burgoyne AM, Somaiah N, Sicklick JK. Gastrointestinal stromal tumors in the setting of multiple tumor syndromes. Curr Opin Oncol. 2014;26:408–14.

    Article  PubMed  Google Scholar 

  12. Bannon AE, Klug LR, Corless CL, Heinrich MC. Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromal tumors. Expert Rev Mol Diagn. 2017;17:445–57.

    Article  CAS  PubMed  Google Scholar 

  13. Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science. 2001;294:173–7.

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Nash P, Tang X, Orlicky S, Chen Q, Gertler FB, Mendenhall MD. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature. 2001;21:514–21.

    Article  ADS  Google Scholar 

  15. Welcker M, Singer J, Loeb KR, Grim J, Bloecher A, Gurien-West M. Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol Cell. 2003;12:381–92.

    Article  CAS  PubMed  Google Scholar 

  16. Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006;6(6):369–81.

    Article  CAS  PubMed  Google Scholar 

  17. Koga Y, Iwatsuki M, Yamashita K, Kiyozumi Y, Kurashige J, Masuda T. The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors. Gastric Cancer. 2019;22:1100–8.

    Article  CAS  PubMed  Google Scholar 

  18. Mao JH, Kim IJ, Wu D, Climent J, Kang HC, DelRosario R. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science. 2008;321:1499–502.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res. 2017;77:2512–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005;121:1085–95.

    Article  CAS  PubMed  Google Scholar 

  21. Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 2007;27:4006–17.

    Article  CAS  PubMed  Google Scholar 

  22. Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011;471:104–9.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471:110–4.

    Article  ADS  CAS  PubMed  Google Scholar 

  24. He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P, Garnett MJ, McDermott U. Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. Cancer Discov. 2013;3:324–37.

    Article  CAS  PubMed  Google Scholar 

  25. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39:1411–9.

    Article  PubMed  Google Scholar 

  26. Rutkowski P, Bylina E, Wozniak A, Nowecki ZI, Osuch C, Matlok M. Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour—the impact of tumour rupture on patient outcomes. Eur J Surg Oncol. 2011;37:890–6.

    Article  CAS  PubMed  Google Scholar 

  27. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–78.

    Article  CAS  PubMed  Google Scholar 

  28. Nishida T, Sato S, Ozaka M, Nakahara Y, Komatsu Y, Kondo M. Long-term adjuvant therapy for high-risk gastrointestinal stromal tumors in the real world. Gastric Cancer. 2022;25:956–65.

    Article  CAS  PubMed  Google Scholar 

  29. Fu Y, Hao H, Guo L, Yang G, Zhang X. Retrospective analysis of 85 cases of intermediate-risk gastrointestinal stromal tumor. Oncotarget. 2017;8:10136–44.

    Article  PubMed  Google Scholar 

  30. Blay JY, Perol D, Le Cesne A. Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors. Ann Oncol. 2012;23:1659–65.

    Article  PubMed  Google Scholar 

  31. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357–64.

    Article  CAS  PubMed  Google Scholar 

  32. G. Gastrointestinal Stromal Tumor Meta-Analysis. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010;28:1247–53.

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

    Article  CAS  PubMed  Google Scholar 

  34. Tarn C, Merkel E, Canutescu AA, Shen W, Skorobogatko Y, Heslin MJ. Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling. Clin Cancer Res. 2005;11:3668–77.

    Article  CAS  PubMed  Google Scholar 

  35. Garcia-Valverde A, Rosell J, Sayols S, Gomez-Peregrina D, Pilco-Janeta DF, Olivares-Rivas I. E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor. Oncogene. 2021;40:6614–26.

    Article  CAS  PubMed  Google Scholar 

  36. Yeh CH, Bellon M, Nicot C. FBXW7: a critical tumor suppressor of human cancers. Mol Cancer. 2018;17:115.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Eto K, Iwatsuki M, Watanabe M, Ishimoto T, Ida S, Imamura Y. The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway. Int J Cancer. 2015;136:1537–45.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang J, Chen K, Tang Y, Luan X, Zheng X, Lu X. LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway. Cell Death Dis. 2021;12:367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Song S, Chen Q, Li Y, Lei G, Scott A, Huo L. Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma. Gut. 2021;70:2238–48.

    Article  CAS  PubMed  Google Scholar 

  40. Li C, Deng C, Pan G, Wang X, Zhang K, Dong Z. Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer. J Exp Clin Cancer Res. 2020;39:230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kurashige J, Watanabe M, Iwatsuki M, Kinoshita K, Saito S, Hiyoshi Y, Kamohara H, Baba Y, Mimori K, Baba H. Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in oesophageal squamous cell carcinoma. Br J Cancer. 2012;106:182–8.

    Article  CAS  PubMed  Google Scholar 

  42. Iwatsuki M, Mimori K, Ishii H, Yokobori T, Takatsuno Y, Sato T. Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: clinical significance. Int J Cancer. 2010;126:1828–37.

    Article  CAS  PubMed  Google Scholar 

  43. Yokobori T, Mimori K, Iwatsuki M, Ishii H, Tanaka F, Sato T. Copy number loss of FBXW7 is related to gene expression and poor prognosis in esophageal squamous cell carcinoma. Int J Oncol. 2012;41:253–9.

    CAS  PubMed  Google Scholar 

  44. Akhoondi S, Lindstrom L, Widschwendter M, Corcoran M, Bergh J, Spruck C. Inactivation of FBXW7/hCDC4-beta expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer. Breast Cancer Res. 2010;12:R105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kitade S, Onoyama I, Kobayashi H, Yagi H, Yoshida S, Kato M. FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors. Cancer Sci. 2016;107:1399–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Nobuhiro Takiguchi and Dr. Atsuhiko Maki for providing clinical samples. The authors also thank Ms. Yasuda and Ms. Ogata for their excellent technical assistance.

Funding

This work was supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant numbers 20K07594). JST SPRING, Grant Number JPMJSP2127 (to XY.W.).

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan

    Xiyu Wu, Masaaki Iwatsuki & Hideo Baba

  2. Department of Rehabilitation, Hospitality Care Garden Seisei Rehabilitation Hospital, Kasuga, Japan

    Masakazu Takaki

  3. Department of Gastroenterological Surgery, Osaka University, Suita, Japan

    Takuro Saito

  4. Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan

    Tsutomu Hayashi

  5. Department of Surgery, Kobe City Medical Center General Hospital, Kobe, Japan

    Masato Kondo

  6. Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yoshiharu Sakai

  7. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Tokyo, Japan

    Naoto Gotohda

  8. Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan

    Eiji Tanaka

  9. Department of Surgery, Japan Community Health-Care Organization Osaka Hospital, Osaka, Japan

    Toshirou Nishida

Authors
  1. Xiyu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masaaki Iwatsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masakazu Takaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takuro Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsutomu Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masato Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiharu Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoto Gotohda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eiji Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toshirou Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hideo Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XYW performed experiments and analyzed the data and wrote the manuscript. MI and XYW designed the research; MT, TS, TH, MK, YS, NG, ET, and TN provided clinical samples; the author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Masaaki Iwatsuki.

Ethics declarations

Conflict of interest

The authors report no conflicts of interest.

Ethical approval

Ethics approval of this study was granted by the ethics committee at Kumamoto University Hospital (approval numbers: 2143) The study was conducted in accordance with the Declaration of Helsinki principles.

Consent for publication

Not applicable.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 15605 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Iwatsuki, M., Takaki, M. et al. FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1. Gastric Cancer 27, 235–247 (2024). https://doi.org/10.1007/s10120-023-01454-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10120-023-01454-6

Keywords

Search

Navigation