Targeted therapies in mutant BRAF melanoma

描述(申请人提供)：RAF抑制剂vemurafenib(PLX4032/Zelboraf)和Dradfenib是目前治疗晚期突变BRAF黑色素瘤的一线选择。目的通过免疫组织化学方法检测维莫拉非尼/达普拉非尼对ERK1/2信号通路的抑制程度，发现患者对维莫拉非尼/达普拉非尼的反应超过80%。然而，目前RAF抑制剂的长期疗效受到突变BRAF细胞获得性耐药和野生型BRAF细胞ERK1/2反常激活的限制。在这项建议中，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的BRAF黑色素瘤细胞中ERK1/2通路的活性。我们利用这个系统提供了对维莫拉非尼获得性耐药的新的机制洞察力。我们还表明，一类新的RAF抑制剂不会引起矛盾的ERK1/2激活，可能会抑制对维莫拉非尼耐药的黑色素瘤细胞的生长。在这里，我们将建议进一步确定维莫拉非尼耐药的潜在机制，并确定对这类新的RAF抑制剂的耐药效果和模式。在我们的实验完成后，我们希望为突变型BRAF黑色素瘤的新一线治疗和vemurafenib/dradfenib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.