FOXD3 up-regulation and ERBB3 signaling as an adaptive response to BRAF inhibitors in melanoma

项目摘要 黑色素瘤是最致命的皮肤癌。我们的目标是了解 致癌信号和耐药性的研究，以改善目前的治疗 选项.丝氨酸/苏氨酸激酶BRAF在约50%的黑素瘤中发生体细胞突变， 驱动MEK-ERK 1/2信号传导的过度激活、异常生长和侵袭。虽然BRAF和 MEK抑制剂现在是晚期突变V600 E BRAF黑色素瘤的一线治疗， 它们只能延缓死亡。因此，我们必须了解如何建立BRAF+MEK抑制剂 治疗方法，并确定如何将它们与免疫检查点药物结合起来， 阻断T细胞作用。在上一轮的研究中，我们发现FOXD 3的上调， ErbB 3信号传导是对BRAF抑制剂的适应性反应，促进药物耐受状态 突变型BRAF黑色素瘤此外，我们发现抑制ErbB 3增强了这种作用， BRAF抑制剂在突变型BRAF黑色素瘤中的作用。在目前的提案中，我们的目标是确定 突变型BRAF黑色素瘤中FOXD 3的调节机制，测试表观遗传 BET/BRD抑制剂将阻断对BRAF+MEK抑制剂的适应性反应，并改变肿瘤细胞的生长。 微环境，并确定FOXD 3表达如何改变细胞的浸润/激活状态。 肿瘤相关免疫细胞群和推定免疫检查点的表达 proteins.在我们的实验完成后，我们希望已经确定了肿瘤和间质 用于对靶向治疗的适应性应答的标记物和告知未来的组合靶向治疗 突变型BRAF黑色素瘤中表观遗传抑制剂和基于免疫治疗策略。

Project Summary Melanoma is the deadliest form of skin cancer. We aim to understand mechanisms underlying oncogenic signaling and drug resistance in melanoma in order to improve the current treatment options. The serine/threonine kinase, BRAF, is somatically mutated in ~50% of melanomas and drives hyper-activation of MEK-ERK1/2 signaling, aberrant growth and invasion. While BRAF and MEK inhibitors are now first-line therapy for advanced-stage mutant V600E BRAF melanomas, they only delay mortality. Thus, we must understand how to build on BRAF+MEK inhibitor treatments and determine how to combine them with immune checkpoint agents, which remove the blocks on T cell action. In the previous cycle of this grant, we showed that up-regulation of FOXD3- ErbB3 signaling is an adaptive response to BRAF inhibitors that promotes a state of drug tolerance in mutant BRAF melanoma. Furthermore, we showed that inhibition of ErbB3 enhanced the effects of BRAF inhibitors in mutant BRAF melanomas in vivo. In this current proposal, we aim to identify mechanisms regulating FOXD3 in mutant BRAF melanomas, test the possibility that epigenetic BET/BRD inhibitors will block adaptive responses to BRAF+MEK inhibitors and alter the tumor microenvironment, and determine how FOXD3 expression alters the infiltration/activation status of tumor-associated immune cell populations and the expression of putative immune checkpoint proteins. At the completion of our experiments, we expect to have identified tumor and stromal markers for adaptive responses to targeted therapy and informed future combinatorial targeted inhibitor, epigenetic inhibitor and immune-based therapeutic strategies in mutant BRAF melanoma.