Targeting SHP2 Reverses BRAF Inhibitor Tolerance in Anaplastic Thyroid Carcinoma

IF 3 4区医学 Q3 CHEMISTRY, MEDICINAL

Anti-cancer agents in medicinal chemistry Pub Date : 2025-08-08 DOI:10.2174/1871520623666230214093122

Tao Tang, Jie Zhou, Li-Xin Zhang, Gang Yang, Wei-Nan Li, Jian-Jiao Zhu, Yong-Fu Xiong, Jing-Dong Li

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引用次数: 0

Abstract

Background: To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer.

Methods: Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors.

Results: In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo.

Conclusion: The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer. The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

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靶向 SHP2 可逆转无性甲状腺癌对 BRAF 抑制剂的耐受性。

目的：探讨达拉非尼与SHP2抑制剂联合治疗无性甲状腺癌的可能性，为无性甲状腺癌的治疗提供新的治疗策略：首先建立耐药模型，通过qPCR检测相关RTK的表达水平。采用 Western blot 检测对照组、单药组和两药联合组中 Akt 和 MAPK 信号通路的蛋白表达水平。通过转染 siRNA 实现 SHP2 基因沉默，并通过 Western 印迹进行验证。CCK8试剂盒和克隆形成试验用于检测细胞增殖活性。小鼠皮下注射突变型甲状腺癌细胞建立体内模型，然后分为四组。每两天测量一次肿瘤直径。免疫组化法评估小鼠肿瘤中p-ERK、p-AKT和Ki67的表达：本研究首先构建了达拉菲尼耐药的ATC细胞，耐药细胞中RTKs的反应上调，激活了Akt和MER/ERK通路。与Dabrafenib组、SHP099组和DMSO组相比，联合组Akt和MEK/ERK通路的激活明显受到抑制，肿瘤细胞的增殖能力明显降低。为了验证SHP099是否脱靶，我们还通过转染siRNA沉默了SHP2的表达，得到了同样的结果。最后，通过建立小鼠耐药模型，我们证实了达拉非尼和SHP099同样可以在体内发挥强大的抗癌作用：SHP2抑制剂SHP099可通过抑制甲状腺癌RAS信号通路的再激活，有效逆转达拉非尼的耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL

CiteScore

5.10

自引率

3.60%

发文量

323

审稿时长

4-8 weeks

期刊介绍： Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.