Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma.
Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma.
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DOI：
10.1158/1541-7786.mcr-21-0832
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发表时间：
2023-05-01
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甲状腺癌的一个子集，复发性分化型甲状腺癌和间变性甲状腺癌（ATC），难以通过甲状腺切除术和全身治疗来治疗。甲状腺癌中的一种常见突变BRAFV 600 E具有靶向治疗选择;然而，与BRAFV 600 E黑色素瘤相比，甲状腺癌的结果令人失望，因为甲状腺癌很快对BRAFV 600 E抑制剂（BRAFi）产生耐药性。在这里，我们使用RNA测序和分子分析研究了BRAFV 600 E甲状腺癌细胞和患者来源的肿瘤样品中响应BRAFi、维罗非尼诱导的分子途径。BRAFV 600 E甲状腺癌细胞中对BRAFi的诱导性应答和获得性BRAFi抗性均显示JAK/STAT途径的显著活化。功能分析显示BRAFi和JAK/STAT通路抑制剂的组合控制BRAFV 600 E甲状腺癌细胞生长。癌症基因组图谱数据分析表明，JAK/STAT信号传导的有效激活与分化型甲状腺癌患者的复发率较低相关。对低分化甲状腺癌和ATC患者肿瘤RNA表达的分析也支持JAK/STAT信号通路活性增强与预后不良相关。我们的研究表明，JAK/STAT途径在BRAFV 600 E甲状腺癌细胞对BRAFi产生耐药性时被激活，并且该途径是抗癌活性的潜在靶点，并克服甲状腺癌中通常对BRAFi治疗产生的耐药性。
A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared to BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in differentiated thyroid cancer patients. Analysis of tumor RNA expression in poorly differentiated thyroid cancer and ATC patients also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer.