Skip to main content
SpringerLink
Log in

Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thyroid cancer

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Anaplastic thyroid cancer (ATC) is a rare type of thyroid cancer (TC) with no effective therapeutic strategy. Although surgery, chemotherapy and radiation are all available for ATC treatment, the median survival for ATC patients is less than 6 months. In this study, we aimed to study on resistant mechanisms to B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor and identify effective combinational therapy for ATC patients. TC cells were treated with Vemurafenib and cell apoptosis and viability were analyzed by flow cytometry and MTT assay. Monolayer and sphere cells were isolated from ATC cells to detect the mRNA level of stem cell markers and differentiation markers by RT-PCR. Phosphor-STAT3 level in sphere and monolayer cells was tested by Western blotting. The xenotransplantation animal model has established to analyze the anti-tumor effect of Vemurafenib and Stattic combinational therapy. Undifferentiated TC cells were resistant to Vemurafenib treatment. Sphere cells isolated from ATC showed no significant change in cell viability and apoptosis upon Vemurafenib treatment, and expressed a high level of stem cell marker and phosphor-STAT3. STAT3 inhibition enhanced the tumorigenic capacity and increased Vemurafenib sensitivity in ATC cell lines. Stattic significantly enhanced anti-tumor effect of Vemurafenib in mouse model. Our findings demonstrate that the combinational therapy of Vemurafenib and Stattic is an effective therapeutic treatment for ATC patients.

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
Fig. 6

Similar content being viewed by others

Abbreviations

ATC:

Anaplastic thyroid cancer

TC:

thyroid cancer

DTC:

differentiated thyroid cancers

UTC:

undifferentiated thyroid cancer

CSCs:

cancer-stem cells

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

DMSO:

dimethyl sulfoxide

PTC:

papillary thyroid cancer

EMT:

epithelial-mesenchymal transition

BRAF:

B-Raf proto-oncogene serine/threonine kinase

HNSCC:

head and neck squamous cell

References

  1. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30. https://doi.org/10.3322/caac.21387

    Article  Google Scholar 

  2. Schlumberger M, French TN (2011) Targeted therapy in refractory thyroid cancer. Eur J Cancer 47(Suppl 3):S328–S329. https://doi.org/10.1016/S0959-8049(11)70190-3

    Article  PubMed  Google Scholar 

  3. Song YS, Park YJ (2019) Genomic characterization of differentiated thyroid carcinoma. Endocrinol Metab (Seoul) 34:1–10. https://doi.org/10.3803/EnM.2019.34.1.1

    Article  Google Scholar 

  4. Burman KD (2014) Is poorly differentiated thyroid cancer poorly characterized? J Clin Endocrinol Metab 99:1167–1169. https://doi.org/10.1210/jc.2014-1549

    Article  CAS  PubMed  Google Scholar 

  5. Hsu KT, Yu XM, Audhya AW, Jaume JC, Lloyd RV, Miyamoto S, Prolla TA, Chen H (2014) Novel approaches in anaplastic thyroid cancer therapy. Oncologist 19:1148–1155. https://doi.org/10.1634/theoncologist.2014-0182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Granata R, Locati L, Licitra L (2013) Therapeutic strategies in the management of patients with metastatic anaplastic thyroid cancer: review of the current literature. Curr Opin Oncol 25:224–228. https://doi.org/10.1097/CCO.0b013e32835ff44b

    Article  CAS  PubMed  Google Scholar 

  7. Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, Kebebew E, Lee NY, Nikiforov YE, Rosenthal MS, Shah MH, Shaha AR, Tuttle RM, American Thyroid Association Anaplastic Thyroid Cancer Guidelines T (2012) American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22:1104–1139. https://doi.org/10.1089/thy.2012.0302

    Article  PubMed  Google Scholar 

  8. Jiao X, Zhang H, Xu X, Yu Y, Zhang H, Zhang J, Ning L, Hao F, Liu X, Niu M, Chen CT, Chen D, Zhang K (2018) S100A4 knockout sensitizes anaplastic thyroid carcinoma cells harboring BRAFV600E/Mt to Vemurafenib. Cell Physiol Biochem 49:1143–1162. https://doi.org/10.1159/000493296

    Article  CAS  PubMed  Google Scholar 

  9. Chiacchio S, Lorenzoni A, Boni G, Rubello D, Elisei R, Mariani G (2008) Anaplastic thyroid cancer: prevalence, diagnosis and treatment. Minerva Endocrinol 33:341–357

    CAS  PubMed  Google Scholar 

  10. Nagaiah G, Hossain A, Mooney CJ, Parmentier J, Remick SC (2011) Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. J Oncol 2011:542358–542313. https://doi.org/10.1155/2011/542358

    Article  PubMed  PubMed Central  Google Scholar 

  11. Perri F, Lorenzo GD, Scarpati GD, Buonerba C (2011) Anaplastic thyroid carcinoma: a comprehensive review of current and future therapeutic options. World J Clin Oncol 2:150–157. https://doi.org/10.5306/wjco.v2.i3.150

    Article  PubMed  PubMed Central  Google Scholar 

  12. Haghpanah V, Fallah P, Naderi M, Tavakoli R, Soleimani M, Larijani B (2016) Cancer stem-like cell behavior in anaplastic thyroid cancer: a challenging dilemma. Life Sci 146:34–39. https://doi.org/10.1016/j.lfs.2015.12.057

    Article  CAS  PubMed  Google Scholar 

  13. Wang C, Wang Z, Liu W, Ai Z (2019) CD133 promotes the self-renewal capacity of thyroid cancer stem cells through activation of glutamate aspartate transporter SLC1A3 expression. Biochem Biophys Res Commun 511:87–91. https://doi.org/10.1016/j.bbrc.2019.02.023

    Article  CAS  PubMed  Google Scholar 

  14. Shiraiwa K, Matsuse M, Nakazawa Y, Ogi T, Suzuki K, Saenko V, Xu S, Umezawa K, Yamashita S, Tsukamoto K, Mitsutake N (2019) JAK/STAT3 and NF-kappaB signaling pathways regulate cancer stem-cell properties in anaplastic thyroid Cancer cells. Thyroid 29:674–682. https://doi.org/10.1089/thy.2018.0212

    Article  CAS  PubMed  Google Scholar 

  15. Wang K, Li Y, Song N, Che X, Hou K, Xu L, Bai M, Wang Q, Wang Y, Zhou Y, Cao M, Liu Y, Zhang J (2019) Signal transducer and activator of transcription 3 inhibition enhances vemurafenib sensitivity in colon cancers harboring the BRAF(V600E) mutation. J Cell Biochem 120:5315–5325. https://doi.org/10.1002/jcb.27808

    Article  CAS  PubMed  Google Scholar 

  16. Tseng LM, Huang PI, Chen YR, Chen YC, Chou YC, Chen YW, Chang YL, Hsu HS, Lan YT, Chen KH, Chi CW, Chiou SH, Yang DM, Lee CH (2012) Targeting signal transducer and activator of transcription 3 pathway by cucurbitacin I diminishes self-renewing and radiochemoresistant abilities in thyroid cancer-derived CD133+ cells. J Pharmacol Exp Ther 341:410–423. https://doi.org/10.1124/jpet.111.188730

    Article  CAS  PubMed  Google Scholar 

  17. Liu C, Zhang Y, Li J, Wang Y, Ren F, Zhou Y, Wu Y, Feng Y, Zhou Y, Su F, Jia B, Wang D, Chang Z (2015) p15RS/RPRD1A (p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A) interacts with HDAC2 in inhibition of the Wnt/beta-catenin signaling pathway. J Biol Chem 290:9701–9713. https://doi.org/10.1074/jbc.M114.620872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou Y, Slone N, Chrisikos TT, Kyrysyuk O, Babcock RL, Medik YB, Li HS, Kleinerman ES, Watowich SS (2020) Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103(+) conventional dendritic cells. J Immunother Cancer 8. https://doi.org/10.1136/jitc-2019-000474

  19. Liu C, Zha Z, Zhou C, Chen Y, Xia W, Wang YN, Lee HH, Yin Y, Yan M, Chang CW, Chan LC, Qiu Y, Li H, Li CW, Hsu JM, Hsu JL, Wang SC, Ren N, Hung MC (2020) Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma. J Hepatol. https://doi.org/10.1016/j.jhep.2020.09.030

  20. Nucera C, Nehs MA, Nagarkatti SS, Sadow PM, Mekel M, Fischer AH, Lin PS, Bollag GE, Lawler J, Hodin RA, Parangi S (2011) Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer. Oncologist 16:296–309. https://doi.org/10.1634/theoncologist.2010-0317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Danysh BP, Rieger EY, Sinha DK, Evers CV, Cote GJ, Cabanillas ME, Hofmann MC (2016) Long-term vemurafenib treatment drives inhibitor resistance through a spontaneous KRAS G12D mutation in a BRAF V600E papillary thyroid carcinoma model. Oncotarget 7:30907–30923. https://doi.org/10.18632/oncotarget.9023

    Article  PubMed  PubMed Central  Google Scholar 

  22. Byeon HK, Na HJ, Yang YJ, Ko S, Yoon SO, Ku M, Yang J, Kim JW, Ban MJ, Kim JH, Kim DH, Kim JM, Choi EC, Kim CH, Yoon JH, Koh YW (2017) Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation. Oncotarget 8:596–609. https://doi.org/10.18632/oncotarget.13480

    Article  PubMed  Google Scholar 

  23. Giani F, Russo G, Pennisi M, Sciacca L, Frasca F, Pappalardo F (2019) Computational modeling reveals MAP3K8 as mediator of resistance to vemurafenib in thyroid cancer stem cells. Bioinformatics 35:2267–2275. https://doi.org/10.1093/bioinformatics/bty969

    Article  CAS  PubMed  Google Scholar 

  24. Byeon HK, Na HJ, Yang YJ, Kwon HJ, Chang JW, Ban MJ, Kim WS, Shin DY, Lee EJ, Koh YW, Yoon JH, Choi EC (2016) c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition. Mol Carcinog 55:1678–1687. https://doi.org/10.1002/mc.22418

    Article  CAS  PubMed  Google Scholar 

  25. Montero-Conde C, Ruiz-Llorente S, Dominguez JM, Knauf JA, Viale A, Sherman EJ, Ryder M, Ghossein RA, Rosen N, Fagin JA (2013) Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov 3:520–533. https://doi.org/10.1158/2159-8290.CD-12-0531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Adachi M, Cui C, Dodge CT, Bhayani MK, Lai SY (2012) Targeting STAT3 inhibits growth and enhances radiosensitivity in head and neck squamous cell carcinoma. Oral Oncol 48:1220–1226. https://doi.org/10.1016/j.oraloncology.2012.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu J, Li YT, Tian XT, Liu YS, Wu ML, Li PN, Liu J (2020) STAT3 signaling statuses determine the fate of resveratrol-treated anaplastic thyroid cancer cells. Cancer Biomark 27:461–469. https://doi.org/10.3233/CBM-191010

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China

    Ying Wang, Zhigang Hu, Weiyuan Ma & Pengxin Zhao

  2. Quyang People’s Hospital, Taihang Road, Quyang County, Baoding, 071000, Hebei, China

    Yong Niu & Jingwei Su

  3. Xingtai Ninth Hospital, No.163 Jiankang East Road, Julu County, Xingtai, 054000, Hebei, China

    Lingxiang Zhang

Authors
  1. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhigang Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weiyuan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingwei Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lingxiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pengxin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pengxin Zhao.

Ethics declarations

Conflict of interests

Ying Wang, Zhigang Hu, Weiyuan Ma, Yong Niu, Jingwei Su, Lingxiang Zhang and Pengxin Zhao declared that they had no conflict of interests.

Ethical approval

The study was approved by the ethics commitment of the Second Hospital of Hebei Medical University.

Informed consent

Not applicable.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Hu, Z., Ma, W. et al. Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thyroid cancer. Invest New Drugs 39, 764–774 (2021). https://doi.org/10.1007/s10637-020-01024-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-020-01024-y

Keywords

Search

Navigation