Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma (LUAD)

摘要 肺癌是美国头号癌症杀手。我们的团队建议开发个性化的新奇产品 利用肿瘤抑制基因突变创造的脆弱性和机会的治疗策略 在肺癌方面。具体地说，我们专注于肿瘤抑制基因LKB1，它是最常见的突变之一 肺腺癌中的基因；在肺腺癌中检测到15%-25%的LKB1突变，这是一种主要的 肺癌患者亚群。尽管发生的频率、上升轨迹，以及攻击性 由于疾病的性质，LKB1突变的LUAD患者不仅没有靶向治疗药物，而且 对免疫检查点抑制剂反应差，迫切需要开发有效的治疗方法 选择。为了解决这一关键差距，我们修订后的应用程序将利用我们对 LKB1缺失诱导的肿瘤生长调控机制及抗癌免疫抑制研究进展 LKB1突变LUAD患者的创新临床治疗方法。新的初步数据来自 我们的团队发现：1)LKB1的缺失会导致代谢失调，如谷氨酸脱氢酶(GDH) 由FAK激活，导致调节性T细胞增加和免疫抑制；2)LKB1-丢失触发 抑制刺痛是一种关键的先天免疫调节因子，可以被IAP抑制剂逆转，导致重新激活 免疫应答及其强大的体内免疫依赖的抗癌作用；3)FAK在LKB1- 缺乏癌细胞，支持细胞侵袭，抑制免疫渗透。这些结果导致了我们的中央 突变的LKB1可能通过失调的抗癌作用发挥其免疫抑制功能的假说 由关键代谢、先天免疫和基质调节因子调节的免疫循环。瞄准这些人 这些因素可能导致重新激活抗癌免疫的新方法，以用于有效的治疗开发 在LUAD。我们将通过三个高度整合的项目来解决这一假设。项目1将检查该角色 FAK-GDH1轴在LKB1突变LUAD免疫治疗耐药和肿瘤进展中的作用项目2 将利用我们最近发现的LKB1调节的LUAD中的IAP-JAK-STING信号来逆转免疫 用IAP抑制剂抑制，以增强免疫治疗效果。项目3将专注于瞄准FAK- 联合应用LKB1突变型LUAD的临床试验 一种FAK抑制剂和一种免疫检查点抑制剂以及机制研究。这些项目得到了支持 由三个核心组成，其职能是行政(核心1)、分子病理学和免疫学(核心2)和 生物信息学和生物统计学(核心3)。这一高度整合的努力建立在我们的新发现之上 成立了肺癌团队，拥有100多份联合出版物，并拥有强大的机构支持。我们预计 通过新药发现(GDH1抑制剂)、临床新应用推进肺癌治疗策略 IAP抑制剂阶段和FAK靶向联合治疗方法的新的II期临床试验 LKB1突变LUAD的免疫治疗耐药性，并为这一患者群体带来治疗选择。

SUMMARY Lung cancer is the leading cancer killer in the United States. Our team proposes to develop novel personalized therapeutic strategies by exploiting vulnerabilities and opportunities created by alterations in tumor suppressors in lung cancer. Specifically, we focus on the tumor suppressor LKB1, which is one of the most commonly mutated genes in lung adenocarcinoma (LUAD); LKB1 mutations are detected in 15-25% of LUAD, representing a major subpopulation of lung cancer patients. Despite the frequency, upward trajectory of incidence, and aggressive nature of disease, patients with LKB1-mutant LUAD not only have no targeted therapeutics available, but also show poor response to immune checkpoint inhibitors, demanding urgent development of effective therapeutic options. To address this critical gap, our revised application will capitalize on our integrated understanding of LKB1-loss–evoked tumor growth regulatory mechanisms and suppression of anticancer immunity to develop innovative clinical approaches for the treatment of patients with LKB1-mutant LUAD. New preliminary data from our team showed that 1) LKB1 loss allows metabolic dysregulation, such as glutamate dehydrogenase (GDH) activation by FAK, leading to increased regulatory T cells and immune suppression; 2) LKB1-loss-triggered inhibition of STING, a key innate immunity regulator, can be reversed by an IAP inhibitor, leading to reactivated immune response and its potent in vivo immune-dependent anticancer effect; and 3) FAK is activated in LKB1- deficient cancer cells and supports cell invasion and inhibits immune infiltration. These results lead to our central hypothesis that mutated LKB1 may exert its immune suppression function through a dysregulated anti-cancer immunity cycle mediated by key metabolic, innate immunity, and stromal regulatory factors. Targeting these factors may lead to novel approaches to re-activate anticancer immunity for effective therapeutic development in LUAD. We will address this hypothesis through three highly integrated Projects. Project 1 will examine the role of the FAK-GDH1 axis in immunotherapy resistance and tumor progression of LKB1-mutant LUAD. Project 2 will exploit our recently discovered LKB1-regulated IAP-JAK-STING signaling in LUAD to reverse immune suppression with an IAP inhibitor to enhance immunotherapy effect. Project 3 will focus on targeting FAK- mediated primary tumor progression in LKB1-mutant LUAD by performing a clinical trial with the combination of a FAK inhibitor and an immune checkpoint inhibitor coupled with mechanistic studies. The projects are supported by three cores, whose functions are administrative (Core 1), molecular pathology and immunology (Core 2), and bioinformatics and biostatistics (Core 3). This highly integrated effort builds on new discoveries from our established lung cancer team with more than 100 co-publications and with strong institutional support. We expect to advance lung cancer treatment strategies by new agent discovery (GDH1 inhibitors), new application of clinical stage IAP inhibitors, and a new phase II clinical trial of a FAK-targeted combination approach to overcome immunotherapy resistance of LKB1-mutant LUAD and bring treatment options to this patient population.