Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors.
Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors.
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DOI：
10.1111/pcmr.12218
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发表时间：
2014-05
影响因子：
4.3
通讯作者：
Aplin AE
中科院分区：
文献类型：
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作者：
Basile KJ;Le K;Hartsough EJ;Aplin AE
在大多数晚期BRAFV600E黑色素瘤患者中，Vemurafenib和dabrafenib阻断MEK-ERK1/2信号并导致肿瘤消退；然而，获得性耐药和矛盾信号已经推动了更有效和选择性RAF抑制剂的研究。下一代RAF抑制剂，如PLX7904 (PB04)，可以有效抑制BRAFV600E黑色素瘤细胞中的RAF信号传导，而在野生型细胞中没有矛盾的作用。此外，PLX7904阻断表达突变NRAS的vemurafenib耐药BRAFV600E细胞的生长。对vemurafenib和dabrafenib的获得性耐药也经常由突变BRAF剪接变体的表达驱动；因此，我们测试了PLX7904及其临床类似物PLX8394 （PB03）在BRAFV600E剪接变异体介导的vemurafenib耐药细胞中的作用。我们发现悖论打破RAF抑制剂能有效阻断MEK-ERK1/2信号、G1/S细胞周期事件、vemurafenib/ plx4720耐药细胞的生存和生长，这些细胞含有不同的BRAFV600E剪接变体。这些数据支持进一步研究悖论破断RAF抑制剂作为vemurafenib或dabrafenib失败患者的二线治疗选择。
Vemurafenib and dabrafenib block MEK-ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAFV600E melanoma patients; however, acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors. Next generation RAF inhibitors, such as PLX7904 (PB04), effectively inhibit RAF signaling in BRAFV600E melanoma cells without paradoxical effects in wild-type cells. Furthermore, PLX7904 blocks the growth of vemurafenib-resistant BRAFV600E cells that express mutant NRAS. Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation BRAF splice variants; thus, we tested the effects of PLX7904 and its clinical analog, PLX8394 (PB03), in BRAFV600E splice variant-mediated vemurafenib-resistant cells. We show that paradox breaker RAF inhibitors potently block MEK-ERK1/2 signaling, G1/S cell cycle events, survival and growth of vemurafenib/PLX4720-resistant cells harboring distinct BRAFV600E splice variants. These data support the further investigation of paradox-breaker RAF inhibitors as a second-line treatment option for patients failing on vemurafenib or dabrafenib.