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Project 1: Glutaminolytic GDH1 activation-dependent immunotherapy resistance in LKB1-mutant lung adenocarcinoma

项目 1：LKB1 突变型肺腺癌中谷氨酰胺分解 GDH1 激活依赖性免疫治疗耐药性

基本信息

批准号：
10411666
负责人：
Sumin Kang
金额：
$ 43.01万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10411666
关键词：
Adenocarcinoma Cell Anoikis Attenuated Binding CD8-Positive T-Lymphocytes CREB1 gene Cancer Patient Cell Death Cell Line Cell Proliferation Cell Survival Cell physiology Cells Cellular Metabolic Process Cytometry Energy Metabolism Enzymes Focal Adhesion Kinase 1 Genetic Genetic Transcription Genetically Engineered Mouse Genomics Glutamate Dehydrogenase Glutamine Goals Homeostasis Human Immune Immune checkpoint inhibitor Immune system Immunologic Factors Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Lead Ligands Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolism Mitochondria Mus Mutate Mutation Neoplasm Metastasis Oxidation-Reduction PD-1 inhibitors Pathway interactions Patients Phosphorylation Play Post-Translational Protein Processing Production Proteins Receptor Signaling Regulation Regulatory T-Lymphocyte Reporting Resistance Role STK11 gene Signal Transduction Stimulator of Interferon Genes T-Lymphocyte Testing Therapeutic Toxic effect Treatment Efficacy Tumor Immunity Tumor-Derived alpha ketoglutarate anti-cancer attenuation base cancer cell cancer therapy cofactor efficacy evaluation immune checkpoint improved in vivo inhibitor kinase inhibitor lung cancer cell macrophage mutant neoplasm immunotherapy neoplastic cell novel novel therapeutic intervention poliovirus receptor programmed cell death ligand 1 protein expression receptor expression response restoration targeted agent targeted treatment transcription factor tumor tumor growth tumor immunology tumor progression

项目摘要

PROJECT SUMMARY Project 1 of the Emory Lung Cancer P01 application focuses on interrogation of metabolic dysregulation in LKB1- mutant lung adenocarcinoma (LUAD) to overcome immunotherapy resistance. LKB1, which is inactivated in 25% of LUAD, plays an important role in regulating cell metabolism. Elevated glutamine metabolism is critical for cancer progression, but the mechanism by which glutaminolysis is upregulated and contributes to immune escape is still elusive. We found that glutamate dehydrogenase 1 (GDH1), the crucial enzyme in glutaminolysis pathway, induces CamKK2, which substitutes for LKB1 to activate AMPK to manage energy homeostasis and promote metastasis in LKB1-deficient lung cancer. Through kinase inhibitor profiling, we found that focal adhesion kinase (FAK; focus of Project 3) phosphorylates GDH1 at Y135 and activates GDH1 specifically in LKB1 mutated LUAD. To investigate the link between GDH1 signaling and antitumor immunity, we performed immune profiling and demonstrated that GDH1 contributes to promotion of activated regulatory T cells and attenuation of tumor infiltrated CD8 T cells in vivo. Replenishing energy metabolism in LKB1 mutated lung cancer with GDH1 loss by reactivating AMPK reduced the enhanced T cell survival in vitro. Through a genomic profiling of immune checkpoint factors, we also found that GDH1 promotes expression of programmed death-ligand 1 (PD-L1) and poliovirus receptor (PVR), and their potential transcription factor CREB was found to be activated by GDH1-CamKK2-CamK4 signaling. Furthermore, GDH1 loss resulted in increased protein expression of stimulator of interferon genes (STING; focus of Project 2). Inhibition of GDH1 using our novel GDH inhibitor R162 attenuated lung cancer progression and rendered LKB1 mutated LUAD cells vulnerable to activated primary immune cells. Moreover, R162 in combination with PD1 inhibitor further induced cancer cell death compared to single agent treatment, suggesting GDH1 as a promising target to overcome immunotherapy resistance. Thus, our central hypothesis is that FAK activates GDH1 by Y135 phosphorylation specifically in LKB1- mutant LUAD and provides immunotherapy resistance through metabolic, transcriptional, and protein stability regulation. Thus, GDH1 represents a promising anti-cancer target in combination with immunotherapy agents targeting PD-L1/PVR signaling. Three specific aims are proposed: (1) To decipher the mechanism by which FAK-mediated phosphorylation and activation of GDH1 promotes cancer progression in an LKB1-dependent manner; (2) To determine how GDH1 confers immunotherapy resistance by providing metabolic, transcriptional, and protein stability advantages through AMPK, CREB, and STING; and (3) To evaluate the therapeutic efficacy of targeting GDH1 in combination with -PD-L1/-TIGIT-based immunotherapy. Along with Project 2 (STING) and Project 3 (FAK), accomplishing the goals of our project is expected to develop novel GDH1-targeted therapeutic approaches to enhance the response of LKB1-mutant LUAD to immunotherapies.

项目概要埃默里肺癌 P01 申请的项目 1 重点关注 LKB1 代谢失调的研究突变型肺腺癌（LUAD）克服免疫治疗耐药性。 LKB1，25%时失活 LUAD在调节细胞代谢中发挥着重要作用。谷氨酰胺代谢升高对于癌症进展，但谷氨酰胺分解上调并有助于免疫的机制逃脱仍然难以捉摸。我们发现谷氨酸脱氢酶 1 (GDH1)，谷氨酰胺分解中的关键酶途径，诱导 CamKK2，它替代 LKB1 激活 AMPK 来管理能量稳态和促进 LKB1 缺陷型肺癌的转移。通过激酶抑制剂分析，我们发现局灶性粘附激酶（FAK；项目 3 的重点）在 Y135 处磷酸化 GDH1，并在 LKB1 突变 LUAD。为了研究 GDH1 信号传导与抗肿瘤免疫之间的联系，我们进行了免疫分析并证明 GDH1 有助于促进激活的调节性 T 细胞和体内肿瘤浸润的 CD8 T 细胞减弱。补充LKB1突变肺癌的能量代谢重新激活 AMPK 导致 GDH1 丢失，会降低体外增强的 T 细胞存活率。通过基因组分析在免疫检查点因子中，我们还发现GDH1促进程序性死亡配体1的表达 (PD-L1)和脊髓灰质炎病毒受体(PVR)，其潜在的转录因子CREB被发现被激活通过 GDH1-CamKK2-CamK4 信号传导。此外，GDH1 缺失导致以下蛋白表达增加：干扰素基因刺激剂（STING；项目 2 的重点）。使用我们的新型 GDH 抑制剂 R162 抑制 GDH1 减弱肺癌进展并使 LKB1 突变的 LUAD 细胞容易受到激活的原代细胞的影响免疫细胞。此外，与 R162 相比，R162 与 PD1 抑制剂联合使用进一步诱导癌细胞死亡单药治疗，表明 GDH1 作为克服免疫治疗耐药性的有希望的靶点。因此，我们的中心假设是 FAK 通过 Y135 磷酸化（特别是在 LKB1 中）激活 GDH1- 突变 LUAD 并通过代谢、转录和蛋白质稳定性提供免疫治疗耐药性规定。因此，GDH1 代表了与免疫治疗药物联合使用的一个有前景的抗癌靶点靶向 PD-L1/PVR 信号传导。提出了三个具体目标：（1）破译其机制 FAK 介导的 GDH1 磷酸化和激活促进 LKB1 依赖性癌症进展方式; (2) 确定 GDH1 如何通过提供代谢、转录、通过 AMPK、CREB 和 STING 获得蛋白质稳定性优势； (3)评价治疗效果靶向 GDH1 与基于 α-PD-L1/α-TIGIT 的免疫疗法相结合。与项目 2 (STING) 一起和项目 3 (FAK)，实现我们项目的目标预计将开发新型 GDH1 靶向药物增强 LKB1 突变 LUAD 对免疫疗法反应的治疗方法。