Targeted therapies in mutant BRAF melanoma

描述（由申请人提供）：RAF抑制剂vemurafenib （PLX4032/Zelboraf）和dabrafenib是目前晚期突变BRAF黑色素瘤的一线治疗选择。目的：免疫组织化学染色显示，患者对vemurafenib/dabrafenib的反应与ERK1/2信号抑制超过80%相关。然而，目前的RAF抑制剂的长期疗效受到突变型BRAF细胞的获得性耐药和野生型BRAF细胞中ERK1/2的矛盾激活的限制。在本提案中，我们概述了一种新的体内报告系统，以非侵入性，定量和时间的方式测量突变BRAF黑色素瘤细胞中的ERK1/2通路活性。我们利用该系统提供了对vemurafenib获得性耐药的新机制。我们还表明，一类新的RAF抑制剂不会引起矛盾的ERK1/2激活，可能会抑制vemurafenib耐药黑色素瘤细胞的生长。在这里，我们将提出进一步确定对vemurafenib耐药的机制，并确定对这类新型RAF抑制剂的作用和耐药模式。在我们的实验完成后，我们期望为突变型BRAF黑色素瘤的新一线治疗和vemurafenib/dabrafenib耐药黑色素瘤的二线治疗方案提供临床前基础。

DESCRIPTION (provided by applicant): The RAF inhibitors, vemurafenib (PLX4032/Zelboraf) and dabrafenib, are the current first-line treatment options for late-stage mutant BRAF melanoma. Objective responses to vemurafenib/dabrafenib in patients are associated with greater than 80% inhibition of ERK1/2 signaling, as measured by immunohistochemical staining. However, the long-term efficacy of current RAF inhibitors is limited by acquired resistance in mutant BRAF cells and paradoxical ERK1/2 activation in wild-type BRAF cells. In this proposal, we outline a novel in vivo reporter system to measure ERK1/2 pathway activity in a non-invasive, quantitative and temporal manner in mutant BRAF melanoma cells. We have utilized this system to provide novel mechanistic insight into acquired resistance to vemurafenib. We also show that a new class of RAF inhibitors that do not elicit paradoxical ERK1/2 activation may provide inhibits growth of vemurafenib-resistant melanoma cells. Here, we will propose to further define mechanisms underlying resistance to vemurafenib, and to determine the effects and modes of resistance to this new class of RAF inhibitors. At the completion of our experiments, we expect to have provided the preclinical basis for new first-line for mutant BRAF melanoma and second-line treatment options for vemurafenib/dabrafenib-resistant melanomas.