Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells
Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells
复制标题
DOI：
10.1111/pcmr.12092
复制
发表时间：
2013-07-01
影响因子：
4.3
通讯作者：
Aplin, Andrew E.
中科院分区：
文献类型：
--
作者：
Le, Kaitlyn;Blomain, Erik S.;Aplin, Andrew E.
RAF抑制剂vemurafenib在突变型BRAF黑色素瘤患者中实现了显著的临床应答。然而，vemurafenib的负担是获得性耐药性和与其在野生型BRAF细胞中ERK 1/2通路的反常激活相关的副作用。这种矛盾的作用推动了一类新的RAF抑制剂的开发。在这里，我们测试了这些选择性的，非悖论诱导RAF抑制剂之一，称为悖论断路器-04（PB 04）或PLX 7904。与其设计一致，PB 04能够有效抑制突变型BRAF黑色素瘤细胞中ERK 1/2的激活，但不会过度激活突变型RAS表达细胞中的ERK 1/2。重要的是，PB 04抑制突变型BRAF黑色素瘤细胞中的ERK 1/2磷酸化，所述突变型BRAF黑色素瘤细胞具有对维罗非尼/PLX 4720的获得性抗性，所述获得性抗性由NRAS中的继发突变介导。与ERK 1/2再激活驱动恶性特性的重新获得一致，PB 04促进细胞凋亡并抑制突变型N-RAS介导的维罗非尼耐药细胞进入S期和锚定非依赖性生长。这些数据表明，矛盾打破RAF抑制剂作为获得性维罗非尼耐药患者队列的二线选择可能具有临床有效性。
The RAF inhibitor vemurafenib achieves remarkable clinical responses in mutant BRAF melanoma patients. However, vemurafenib is burdened by acquired drug resistance and by the side effects associated with its paradoxical activation of the ERK1/2 pathway in wild-type BRAF cells. This paradoxical effect has driven the development of a new class of RAF inhibitors. Here, we tested one of these selective, non-paradox-inducing RAF inhibitors termed paradox-breaker-04 (PB04) or PLX7904. Consistent with its design, PB04 is able to efficiently inhibit activation of ERK1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK1/2 in mutant RAS-expressing cells. Importantly, PB04 inhibited ERK1/2 phosphorylation in mutant BRAF melanoma cells with acquired resistance to vemurafenib/PLX4720 that is mediated by a secondary mutation in NRAS. Consistent with ERK1/2 reactivation driving the re-acquisition of malignant properties, PB04 promoted apoptosis and inhibited entry into S phase and anchorage-independent growth in mutant N-RAS-mediated vemurafenib-resistant cells. These data indicate that paradox-breaker RAF inhibitors may be clinically effective as a second-line option in a cohort of acquired vemurafenib-resistant patients.