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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2023

Open Access 01-12-2023 | Thyroid Cancer | Research

Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies

Authors: Dong Chen, Xi Su, Lizhang Zhu, Hao Jia, Bin Han, Haibo Chen, Qingzhuang Liang, Chenchen Hu, Hao Yang, Lisa Liu, Peng Li, Wei Wei, Yongsheng Zhao

Published in: Journal of Translational Medicine | Issue 1/2023

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Abstract

Backgrounds

Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed.

Methods

Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively.

Results

We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone.

Conclusions

These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.
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Metadata
Title
Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies
Authors
Dong Chen
Xi Su
Lizhang Zhu
Hao Jia
Bin Han
Haibo Chen
Qingzhuang Liang
Chenchen Hu
Hao Yang
Lisa Liu
Peng Li
Wei Wei
Yongsheng Zhao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2023
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03848-z

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