Vemurafenib, an inhibitor of mutant BRAF activity, is a promising anticancer agent for patients with BRAF-mutant metastatic melanoma. However, it is less effective in BRAF-mutant thyroid cancer, and the reason for this discrepancy is not yet fully elucidated. By RNA sequencing analysis, we identified vascular cell adhesion molecular-1 (VCAM-1) to be highly upregulated in both time- and dose-dependent manners during BRAF inhibition (BRAFi) in a BRAF-mutant papillary thyroid cancer cell line (BCPAP). Cell cytotoxicity and apoptosis assays showed that knockdown of the induced VCAM-1 in BCPAP cells augmented the antitumor effects of vemurafenib, with decreased IC50 values of 1.4 to 0.8 μM. Meanwhile, overexpression of VCAM-1 in a BRAF-mutant anaplastic thyroid cancer cell line (FRO) reduced the sensitivity to vemurafenib, with increased IC50 values of 1.9 to 5.8 μM. Further investigation showed that PI3K-Akt-mTOR pathway was activated during BRAFi. Co-treatment with Akt signaling inhibitor MK2206 decreased the induced expression of VCAM-1 during BRAFi. This combination further improved the efficacy of vemurafenib. Moreover, VCAM-1 promoted migration and invasion in thyroid cancer cells in vitro, which was also indicated in thyroid cancer patients. The present study is the first to demonstrate that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. Targeting the PI3K-Akt-mTOR pathway–mediated VCAM-1 response may be an alternative strategy to sensitize BRAF-mutant thyroid cancers to vemurafenib.

Vemurafenib是BRAF突变活性的抑制剂，是BRAF突变型转移性黑色素瘤患者的有希望的抗癌药。但是，它在BRAF突变型甲状腺癌中疗效较差，这种差异的原因尚未完全阐明。通过RNA测序分析，我们发现在BRAF突变型乳头状甲状腺癌细胞系（BCPAP）的BRAF抑制（BRAFi）期间，血管细胞粘附分子1（VCAM-1）呈时间和剂量依赖性。 。细胞的细胞毒性和凋亡分析表明，BCPAP细胞中诱导的VCAM-1的敲低增强了维罗非尼的抗肿瘤作用，IC50值降低了1.4至0.8μM。同时，BRAF突变型变性甲状腺癌癌细胞系（FRO）中VCAM-1的过表达降低了对维罗非尼的敏感性，IC50值增加到1.9至5.8μM。进一步的研究表明PI3K-Akt-mTOR通路在BRAFi期间被激活。与Akt信号抑制剂MK2206共同治疗可降低BRAFi期间VCAM-1的诱导表达。这种组合进一步提高了维罗非尼的疗效。此外，VCAM-1促进甲状腺癌细胞的迁移和侵袭在体外，这也适用于甲状腺癌患者。本研究是第一个证明VCAM-1在用vemurafenib治疗的甲状腺癌细胞中被上调并且有助于BRAF突变型甲状腺癌细胞对vemurafenib产生耐药性的研究。靶向PI3K-Akt-mTOR途径介导的VCAM-1反应可能是使BRAF突变型甲状腺癌对维罗非尼敏感的另一种策略。