JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.
JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.
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DOI：
10.1038/celldisc.2016.28
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发表时间：
2016
期刊：
影响因子：
33.5
通讯作者：
Graeber, Thomas G.
中科院分区：
文献类型：
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作者：
Titz, Bjoern;Lomova, Anastasia;Le, Allison;Hugo, Willy;Kong, Xiangju;ten Hoeve, Johanna;Friedman, Michael;Shi, Hubing;Moriceau, Gatien;Song, Chunying;Hong, Aayoung;Atefi, Mohammad;Li, Richard;Komisopoulou, Evangelia;Ribas, Antoni;Lo, Roger S.;Graeber, Thomas G.
BRAFV 600突变型黑色素瘤中对BRAF抑制剂获得性耐药的一个重要机制与受体酪氨酸激酶的上调有关。有证据表明，这种抵抗机制是更复杂的细胞适应过程的一部分。使用综合策略，我们发现这种机制引起广泛的转录组学，（磷酸化）蛋白质组学和表型改变，伴随着细胞向去分化，间充质和侵入性状态的转变。即使是短期的BRAF抑制剂暴露也会导致早期的适应性分化状态变化，其特征在于缓慢循环的持续状态。早期持续状态与晚期增殖性抵抗状态不同。然而，这两种分化状态共享共同的信号转导改变，包括JUN上调。受相似性的启发，我们发现BRAF和JUN的共靶向在杀死完全耐药细胞方面具有协同作用;并且当预先使用时，共靶向大大削弱了持久亚群的形成。我们证实，JUN上调是临床治疗的患者肿瘤中对BRAF抑制剂治疗的常见反应。我们的研究结果表明，早期和晚期适应状态之间共享的事件提供了候选的前期共同治疗目标。
A prominent mechanism of acquired resistance to BRAF inhibitors in BRAFV600-mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change—characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets.
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影响因子：
8
作者：
Basile, K. J.;Abel, E. V.;Aplin, A. E.
通讯作者：
Aplin, A. E.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.2
作者：
Alonso, Soledad R.;Tracey, Lorraine;Rodriguez-Peralto, Jose L.
通讯作者：
Rodriguez-Peralto, Jose L.
影响因子：
8
作者：
Gurzov, E. N.;Bakiri, L.;Izquierdo, M.
通讯作者：
Izquierdo, M.
影响因子：
64.8
作者：
通讯作者：
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