Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thy
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PHASE I STUDIES
Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thyroid cancer Ying Wang 1 & Zhigang Hu 1 & Weiyuan Ma 1 & Yong Niu 2 & Jingwei Su 2 & Lingxiang Zhang 3 & Pengxin Zhao 1 Received: 10 September 2020 / Accepted: 20 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Anaplastic thyroid cancer . Cancer stem cell . Stattic . Vemurafenib . STAT3
Introduction Thyroid cancer is an endocrine-related cancer, which is the most common endocrine malignancy [1]. Thyroid cancers were classified into different subtypes based on their differentiated capability and histopathological characteristics [2]. For example, differentiated thyroid cancers (DTC) and papillary thyroid cancer (PTC), which accounts for around 80% of thyroid cancers [3], are two malignancies that originate from follicular and parafollicular cells, respectively. Anaplastic thyroid cancer (ATC) is a small subset of undifferentiated thyroid
* Pengxin Zhao [email protected] 1
The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, Hebei, China
2
Quyang People’s Hospital, Taihang Road, Quyang County, Baoding 071000, Hebei, China
3
Xingtai Ninth Hospital, No.163 Jiankang East Road, Julu County, Xingtai 054000, Hebei, China
cancer (UTC) in thyroid cancer, which is one of the most leading causes of thyroid cancer-related death with no effective available therapeutic options [4, 5]. Recently, several therapeutic approaches
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