Src-mediated regulation of the PI3K pathway in advanced papillary and anaplastic thyroid cancer.
Src-mediated regulation of the PI3K pathway in advanced papillary and anaplastic thyroid cancer.
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DOI：
10.1038/s41389-017-0015-5
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发表时间：
2018-02-28
期刊：
影响因子：
6.2
通讯作者：
Schweppe RE
中科院分区：
文献类型：
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作者：
Beadnell TC;Nassar KW;Rose MM;Clark EG;Danysh BP;Hofmann MC;Pozdeyev N;Schweppe RE
晚期乳头状癌和间变性甲状腺癌继续受到预后不佳的困扰，这是这些癌症有效治疗有限的结果。由于在甲状腺癌中有很高比例的MAPK通路突变，MAPK通路已成为甲状腺癌治疗干预的重点。不幸的是，与黑色素瘤不同，在甲状腺癌患者中还没有观察到对MAPK通路抑制的类似反应。为了解决这个问题，我们专注于靶向非受体酪氨酸激酶，我们和其他人已经证明了靶向Src会在体外和体内抑制生长、侵袭和迁移，这可以通过联合抑制Src和MAPK通路来增强。因此，我们对代表常见致癌驱动因素的一组甲状腺癌细胞株(BRAF、RAS和PIK3CA)的联合治疗效果进行了研究。有趣的是，在同时抑制MAPK和PI3K通路的细胞系中，联合抑制Src和MAPK通路可以克服内在的达沙替尼耐药，我们表明这可能是由于Src在这些反应细胞中调节PI3K通路。有趣的是，我们已经将rpS6的下游磷酸化定位为反应的关键生物标志物，而保持rpS6磷酸化的细胞可能代表耐药的持续者。总之，联合抑制Src和MAPK通路有望改善BRAF和RAS突变的晚期甲状腺癌患者的总体生存，而PI3K通路的激活和rpS6磷酸化是接受该疗法治疗的患者的重要生物标志物。
Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non-receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway. Therefore, we examined the efficacy of the combination therapy across a panel of thyroid cancer cell lines representing common oncogenic drivers (BRAF, RAS, and PIK3CA). Interestingly, combined inhibition of Src and the MAPK pathway overcomes intrinsic dasatinib resistance in cell lines where both the MAPK and PI3K pathways are inhibited, which we show is likely due to the regulation of the PI3K pathway by Src in these responsive cells. Interestingly, we have mapped downstream phosphorylation of rpS6 as a key biomarker of response, and cells that maintain rpS6 phosphorylation likely represent drug tolerant persisters. Altogether, the combined inhibition of Src and the MAPK pathway holds great promise for improving the overall survival of advanced thyroid cancer patients with BRAF and RAS mutations, and activation of the PI3K pathway and rpS6 phosphorylation represent important biomarkers of response for patients treated with this therapy.
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DOI：
10.1158/1541-7786.mcr-14-0158-t
发表时间：
2014-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Charles RP;Silva J;Iezza G;Phillips WA;McMahon M
通讯作者：
McMahon M
影响因子：
11.2
作者：
Iadevaia S;Lu Y;Morales FC;Mills GB;Ram PT
通讯作者：
Ram PT
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
9
作者：
通讯作者：
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
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