Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells.
Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells.
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DOI：
10.1038/onc.2011.424
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发表时间：
2012-05-10
期刊：
影响因子：
8
通讯作者：
Aplin, A. E.
中科院分区：
文献类型：
--
作者：
Basile, K. J.;Abel, E. V.;Aplin, A. E.
由突变B-RAF驱动的黑素瘤细胞对化疗治疗具有高度抗性。最近PLX 4032/RG 7204/Vemurafenib的1期结果，选择性抑制突变B-RAF细胞中的B-RAF/MEK/ERK 1/2信号传导，为这一苦苦挣扎的领域提供了鼓励。在1-3期研究中，几乎所有患者都至少看到了一些缓解，总体缓解率在81%至48%之间。然而，尽管最初的肿瘤缩小，试验中的大多数应答者随着时间的推移经历了肿瘤复发。这些发现表明，内在和获得性耐药可能会影响PLX 4032的临床疗效。优化PLX 4032活性以提高缓解率并了解为什么一些B-RAF突变患者没有反应至关重要。我们以前已经表明，干细胞因子，叉头盒D3（FOXD 3），在突变B-RAF黑色素瘤细胞中抑制B-RAF-MEK信号转导后上调。在这里，我们表明用PLX 4032和PLX 4720（PLX 4032的非临床工具化合物）处理后FOXD 3的上调赋予对细胞死亡的抗性。小干扰RNA（siRNA）介导的FOXD 3敲低显著增强了突变B-RAF黑色素瘤细胞系中PLX 4032/4720处理后的细胞死亡反应。此外，在非粘附条件下，PLX 4720处理后FOXD 3的上调减弱，并与增强的细胞死亡相关。非粘附细胞中FOXD 3的异位表达显著减少了响应于PLX 4720处理的细胞死亡。总之，这些数据表明FOXD 3的上调是对RAF抑制剂的适应性反应，其促进了耐药性的状态。
Melanoma cells driven by mutant B-RAF are highly resistant to chemotherapeutic treatments. Recent Phase 1 results with PLX4032/RG7204/Vemurafenib, which selectively inhibits B-RAF/MEK/ERK1/2 signaling in mutant B-RAF cells, has given encouragement to this struggling field. Nearly all patients in the phase 1–3 studies saw at least some response and the overall response rates were in between 81 and 48%. However, despite initial tumor shrinkage, most responders in the trial experienced tumor relapse over time. These findings indicate that both intrinsic and acquired resistance may affect the clinical efficacy of PLX4032. It is critical to optimize PLX4032 activity to improve response rates and understand why some patients with the B-RAF mutation do not respond. We have previously shown that the stemness factor, Forkhead box D3 (FOXD3), is up-regulated following inhibition of B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that up-regulation of FOXD3 following treatment with PLX4032 and PLX4720 (the non-clinical tool compound for PLX4032) confers resistance to cell death. Small interfering RNA (siRNA)-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032/4720 treatment in mutant B-RAF melanoma cell lines. Additionally, up-regulation of FOXD3 after PLX4720 treatment was attenuated in non-adherent conditions and correlated with enhanced cell death. Ectopic expression of FOXD3 in non-adherent cells significantly reduced cell death in response to PLX4720 treatment. Together, these data indicate that up-regulation of FOXD3 is an adaptive response to RAF inhibitors that promotes a state of drug resistance.
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影响因子：
64.8
作者：
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影响因子：
64.8
作者：
Johannessen, Cory M.;Boehm, Jesse S.;Kim, So Young;Thomas, Sapana R.;Wardwell, Leslie;Johnson, Laura A.;Emery, Caroline M.;Stransky, Nicolas;Cogdill, Alexandria P.;Barretina, Jordi;Caponigro, Giordano;Hieronymus, Haley;Murray, Ryan R.;Salehi-Ashtiani, Kourosh;Hill, David E.;Vidal, Marc;Zhao, Jean J.;Yang, Xiaoping;Alkan, Ozan;Kim, Sungjoon;Harris, Jennifer L.;Wilson, Christopher J.;Myer, Vic E.;Finan, Peter M.;Root, David E.;Roberts, Thomas M.;Golub, Todd;Flaherty, Keith T.;Dummer, Reinhard;Weber, Barbara L.;Sellers, William R.;Schlegel, Robert;Wargo, Jennifer A.;Hahn, William C.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
4.8
作者：
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通讯作者：
Pei, Duanqing
DOI：
10.1073/pnas.0711741105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Tsai, James;Lee, John T.;Bollag, Gideon
通讯作者：
Bollag, Gideon
影响因子：
4.8
作者：
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通讯作者：
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