BRAFV600E 代表一种组成型活性肿瘤激酶，是甲状腺癌中最常见的基因改变。然而，针对 BRAFV600E 的小分子抑制剂的临床疗效往往受到获得性耐药的限制。在这里，我们发现神经/胶质抗原 2 (NG2)，也称为硫酸软骨素蛋白聚糖 4 (CSPG4)，在甲状腺癌中表达上调，并且在 BRAFV600E 驱动的甲状腺癌小鼠模型中，其表达随着肿瘤进展而增加。功能研究表明，NG2敲除几乎不影响肿瘤生长，但显着提高BRAF突变型甲状腺癌细胞对BRAF抑制剂PLX4720的反应。从机制上讲，BRAF 抑制剂阻断 ERK 依赖性反馈可以激活受体酪氨酸激酶 (RTK) 信号传导，导致对该抑制剂产生耐药性。 NG2 敲除减弱了 PLX4720 介导的几种 RTK 的反馈激活，提高了 BRAF 突变型甲状腺癌细胞对该抑制剂的敏感性。基于这一发现，我们提出并论证了一种靶向 NG2 的替代策略，通过将多种激酶抑制剂 (MKI) 索拉非尼或乐伐替尼与 PLX4720 相结合，有效治疗 BRAF 突变型甲状腺癌。因此，本研究揭示了 NG2 促进 BRAF 突变型甲状腺癌细胞对 BRAF 抑制剂产生耐药性的新机制，并为 BRAF 突变型甲状腺癌提供了一种有前景的治疗选择。© 2024。作者。

BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.© 2024. The Author(s).