Stat3-Targeted Therapies Overcome the Acquired Resistance to Vemurafenib in Melanomas
Stat3-Targeted Therapies Overcome the Acquired Resistance to Vemurafenib in Melanomas
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DOI：
10.1038/jid.2013.32
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发表时间：
2013-08-01
影响因子：
6.5
通讯作者：
Cui, Rutao
中科院分区：
文献类型：
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作者：
Liu, Fang;Cao, Juxiang;Cui, Rutao
Vemurafenib（PLX 4032）是Brat的选择性抑制剂，已被美国食品和药物管理局批准用于治疗Braf（V600 E）突变患者的不可切除或转移性黑素瘤。许多接受vemurafenib治疗的患者最初表现出显着的改善，死亡和肿瘤进展的风险均降低。然而，获得性耐药性在先前敏感的细胞中迅速出现。我们试图通过靶向信号转导子和转录激活子3（STAT 3）-配对盒同源异型基因3（PAX 3）-信号传导途径来克服这种抗性，该信号传导途径由于成纤维细胞生长因子2（FGF 2）分泌或激酶活性增加而被上调，具有Braf（V600 E）突变。我们发现Stat 3的激活或PAX 3的过表达诱导黑色素瘤细胞对维罗非尼的耐药性。此外，PAX 3或Stat 3沉默抑制了对维罗非尼具有获得性耐药性的黑素瘤细胞的生长。此外，用Stat 3抑制剂WP 1066处理导致维罗非尼敏感性和耐药性黑色素瘤细胞的生长抑制。值得注意的是，维罗非尼刺激诱导角质形成细胞和成纤维细胞分泌FGF 2，这可能至少部分揭示了靶向Stat 3-PAX 3信号传导以克服对维罗非尼的获得性耐药性的潜在机制。我们的研究结果表明，Stat 3靶向治疗是一种新的治疗策略，以克服在治疗黑色素瘤的获得性耐药威罗菲尼。
Vemurafenib (PLX4032), a selective inhibitor of Brat has been approved by the US Food and Drug Administration for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempted to overcome this resistance by targeting the signal transducer and activator of transcription 3 (STAT3)-paired box homeotic gene 3 (PAX3)-signaling pathway, which is upregulated, owing to fibroblast growth factor 2 (FGF2) secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. In addition, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.