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

总结 肺癌是美国的头号癌症杀手。我们的团队建议开发新颖的个性化 通过利用肿瘤抑制因子改变所产生的脆弱性和机会的治疗策略 在肺癌中。具体来说，我们专注于肿瘤抑制因子LKB 1，这是最常见的突变之一， 肺腺癌（LUAD）中的LKB 1基因;在15-25%的LUAD中检测到LKB 1突变，这代表了肺腺癌的主要特征。 肺癌患者的亚群。尽管发生频率、发病率呈上升趋势， 由于疾病的性质，LKB 1突变型LUAD患者不仅没有可用的靶向治疗， 对免疫检查点抑制剂的反应较差，迫切需要开发有效的治疗药物， 选项.为了解决这一关键差距，我们修改后的应用程序将利用我们对以下方面的综合理解： LKB 1缺失诱发的肿瘤生长调节机制和抗癌免疫抑制 治疗LKB 1突变型LUAD患者的创新临床方法。新的初步数据来自 我们的研究小组发现：1）LKB 1的缺失导致代谢失调，如谷氨酸脱氢酶（GDH） FAK激活，导致调节性T细胞增加和免疫抑制; 2）LKB 1丢失触发 STING是一种关键的先天免疫调节因子，其抑制作用可被IAP抑制剂逆转，导致重新激活的 免疫应答及其有效的体内免疫依赖性抗癌作用;和3）FAK在LKB 1- 缺乏癌细胞并支持细胞侵袭和抑制免疫浸润。这些结果导致我们的中央 突变的LKB 1可能通过失调的抗癌作用发挥其免疫抑制功能的假设 免疫周期由关键代谢、先天免疫和基质调节因子介导。靶向这些 这些因素可能导致新的方法来重新激活抗癌免疫，以实现有效的治疗开发 在LUAD。我们将通过三个高度综合的项目来解决这个假设。项目1将研究 FAK-GDH 1轴在LKB 1突变LUAD的免疫治疗抗性和肿瘤进展中的作用。计划2 将利用我们最近发现的LUAD中LKB 1调节的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将重点针对FAK- 介导的LKB 1突变型LUAD中的原发性肿瘤进展， FAK抑制剂和免疫检查点抑制剂结合机制研究。项目得到支持 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），以及 生物信息学和生物统计学（核心3）。这种高度综合的努力建立在我们的新发现的基础上。 建立了肺癌团队，合作发表了100多篇论文，并得到了强有力的机构支持。我们预计 通过新药发现（GDH 1抑制剂）、临床新应用， 阶段IAP抑制剂，以及一项新的针对FAK的组合方法的II期临床试验，以克服 LKB 1突变型LUAD的免疫治疗抗性，并为该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.