Role of Ly6K in TGF-beta and immune escape pathways of triple negative breast cancer

项目摘要/摘要 我们已经发现，Ly6K的高表达与三阴性乳腺的不良预后有关 癌症(TNBC)。从机制上讲，Ly6K是转化生长因子β信号的激活和表达增加所必需的。 免疫检查点蛋白PD-L1。我们认为生物标记物Ly6K是治疗卵巢癌的理想靶点。 治疗TNBC，因为这种蛋白在正常细胞中不表达，除非在睾丸中，而且不是必需的 对于重要的器官功能，除了精子发生。因此，针对该蛋白治疗TNBC，一种 主要影响女性的疾病，是适当和理想的。我们已经确定了类似药物的小分子，它们 特异性结合Ly6K，抑制体内肿瘤生长。在机制上，它们抑制转化生长因子β信号和PD-1。 L1在TNBC细胞中以Ly6K依赖的方式表达。在这份提案中，我们计划验证这些潜力 人性化PDX模型中的新疗法。这项提议将揭示下游缺失的信令链路 激活转化生长因子β信号转导通路，增加PD-L1的表达。我们预计来自我们的调查结果 研究将改变与治疗TNBC有关的发展疗法领域，将Ly6K定义为 抗转化生长因子β信号转导和抑制PD-L1表达的新靶点。

Project Summary/abstract We have identified that increased expression of Ly6K is associated with poor outcome in triple negative breast cancer (TNBC). Mechanistically, Ly6K is required for activation of TGFβ signaling and increased expression of the immune checkpoint protein PD-L1. We propose that the biomarker Ly6K is an ideal therapeutic target for the treatment of TNBC because this protein is not expressed in normal cells, except in testis, and it is not required for vital organ function, except for spermatogenesis. Thus, targeting this protein for the treatment of TNBC, a disease affecting mostly females, is appropriate and ideal. We have identified small drug-like molecules, which specifically bind to Ly6K and inhibit in vivo tumor growth. Mechanistically, they inhibit TGFβ signaling and PD- L1 expression in TNBC cells in an Ly6K dependent manner. In this proposal, we plan to validate these potential novel therapeutics in a humanized PDX model. This proposal will reveal the missing signaling links downstream of Ly6K, which activate TGFβ signaling and increase PD-L1 expression. We anticipate that the findings from our research will transform the field of developmental therapeutics concerning treatment of TNBC by defining Ly6K as a novel therapeutic target for anti-TGFβ signaling and inhibition of PD-L1 expression.