Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas.
Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas.
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DOI：
10.1158/2159-8290.cd-12-0531
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发表时间：
2013-05
期刊：
影响因子：
28.2
通讯作者：
Fagin JA
中科院分区：
文献类型：
--
作者：
Montero-Conde C;Ruiz-Llorente S;Dominguez JM;Knauf JA;Viale A;Sherman EJ;Ryder M;Ghossein RA;Rosen N;Fagin JA
RAF抑制剂vemurafenib （PLX4032）可提高braf突变转移性黑色素瘤患者的生存率，但对结直肠癌患者的疗效有限。甲状腺癌细胞对RAF抑制剂也相对难治。与黑色素瘤相比，vemurafenib对甲状腺和结直肠癌细胞中MAPK信号的抑制是短暂的。甲状腺细胞ERK的反弹伴随着HER3信号的增加，这是通过转录抑制因子CtBP1和2减少启动子占用，以及神经调节蛋白1的自分泌来诱导HER3转录而引起的。HER激酶抑制剂拉帕替尼可防止MAPK反弹，并使braf突变的甲状腺癌细胞对RAF或MEK抑制剂敏感。这为将ERK通路拮抗剂与反馈再激活HER信号抑制剂联合治疗这种疾病提供了理论依据。由于特异性rtk的优先上调以及它们各自配体的丰度，MAPK抑制剂原发性耐药的决定因素因癌症类型而异。
The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. By contrast to melanomas, inhibition of MAPK signaling by vemurafenib is transient in thyroid and colorectal cancer cells. The rebound in ERK in thyroid cells is accompanied by increased HER3 signaling caused by induction of HER3 transcription through decreased promoter occupancy by the transcriptional repressors CtBP1 and 2, and by autocrine secretion of neuregulin-1. The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MEK inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific RTKs, and the abundance of their respective ligands.