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STK11 loss of function and anti-PD-1 therapy resistance in KRAS-driven lung adenocarcinoma

KRAS 驱动的肺腺癌中 STK11 功能丧失和抗 PD-1 治疗耐药

基本信息

批准号：
10647261
负责人：
David Joseph Seward
金额：
$ 21.88万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-11 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647261
关键词：
Alleles Award Biological Markers Cancer Patient Cancer cell line Cell Line Cells Clinical Research Colorectal Cancer Critical Pathways Cytokine Signaling Data Set Dedications Development FDA approved Flow Cytometry Gene Expression Profile Gene set enrichment analysis Genetic Transcription Genetically Engineered Mouse Genotype Goals Grant Histologic Human IL8 gene Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunotherapeutic agent Immunotherapy Interleukin-2 Interleukin-6 K-ras mouse model KRAS2 gene KRASG12D Knowledge Leukocytes Link Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Modeling Molecular Monitor Monoclonal Antibody Therapy Morbidity - disease rate Mus Mutate Mutation NF-kappa B Neoplasm Metastasis Organ Size Outcome Patients Persons Phenotype Physicians Production Prognosis Protein-Serine-Threonine Kinases Proteins Regulation Reporter Reporting Research Resistance Scientist Serine Signal Transduction Sorting TNF gene Technology Testing Tomatoes Triage Tumor Burden Tumor Suppressor Genes Tumor Suppressor Proteins United States Up-Regulation Verteporfin Work anti-PD-1 anti-PD1 antibodies anti-PD1 therapy career catalyst cytokine in vivo inhibitor interleukin-23 loss of function lung cancer cell malignant breast neoplasm mortality mouse model neoplastic cell novel therapeutic intervention programs recruit research and development responders and non-responders response therapeutic target therapy development transcription factor transcriptome transcriptome sequencing treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Lung cancer remains both prevalent and deadly, emphasizing the need for continued research and therapy development. Advances in immunotherapeutic technologies, including check-point inhibitors such as anti-PD-1 monoclonal antibody therapy, have shown great promise in treating lung cancer patients. Unfortunately, not all patients respond. Recent clinical studies have linked anti-PD-1 therapy resistance with specific combinations of somatic tumor mutations. Notably, patients with KRAS-driven lung adenocarcinomas lacking functional STK11 suffer a worse prognosis, increased rates of metastasis, and marked resistance to anti-PD-1 therapy. Why STK11 loss of function (LoF) correlates with resistance to anti-PD-1 therapy remains unclear. Serine Threonine Kinase 11 (STK11) encodes an important tumor suppressor gene frequently mutated in KRAS-driven lung adenocarcinomas. Our work in human lung cancer cell lines supports STK11-loss-dependent transcriptional induction of tumor cytokines as one mechanism that might impact anti-PD-1 therapy resistance. Specifically, RNAseq analysis indicates activation of Yes-associated protein 1 (YAP1) and Nuclear Factor Kappa B (NFkB) transcription networks occur upon STK11 loss. YAP1 is the ultimate effector in the HIPPO signaling axis, a pathway critical for regulating organ size during development. While YAP1 has previously been linked with regulating tumor cytokine expression, whether its activity is directly regulated by STK11 has yet to be established. NFkB is a master transcription factor essential for regulating numerous cytokines, but as with YAP1, how STK11 might regulate NFkB activity remains unaddressed. We hypothesize that STK11 loss leads to anti-PD-1 therapy resistance by altering immune cell recruitment to the tumor microenvironment via altered tumor cytokine signaling. The workplan we present aims to characterize differential immune cell recruitment in an inducible mouse model of lung cancer as a function of STK11 status and tumor transcriptome. We will leverage immune competent, genetically engineered mice that develop inducible KRAS-driven or KRAS/STK11 LoF lung adenocarcinomas to directly characterize the correlation between tumor genotype, tumor transcriptome, and differential immune cell recruitment. We will then utilize this model to assess strategies for reversing anti-PD-1 therapy resistance. Specifically, we will evaluate antagonizing candidate transcriptional networks downstream of STK11 loss, including YAP1 and NFkB, as strategies to restore an anti-tumor immune microenvironment, potentially rescuing anti-PD1 efficacy in STK11 null tumors. To accomplish this, we will define the extent of STK11-dependent anti-PD-1 resistance displayed by our mice compared with tumors driven by KRAS alone. We will then evaluate whether antagonizing candidate networks reverses the STK11-LoF transcriptional phenotype, and in turn restores the immune cell compliment observed in STK11 WT tumors.

项目概要肺癌仍然普遍且致命，强调需要继续研究和治疗发展。免疫治疗技术的进步，包括抗 PD-1 等检查点抑制剂单克隆抗体疗法在治疗肺癌患者方面显示出巨大的前景。不幸的是，并非所有患者有反应。最近的临床研究已将抗 PD-1 治疗耐药性与特定的组合联系起来体细胞肿瘤突变。值得注意的是，KRAS 驱动的肺腺癌患者缺乏功能性 STK11 预后较差，转移率增加，并且对抗 PD-1 治疗具有显着耐药性。为什么 STK11 功能丧失 (LoF) 与抗 PD-1 治疗耐药的相关性尚不清楚。丝氨酸苏氨酸激酶 11 (STK11) 编码一种重要的肿瘤抑制基因，该基因在 KRAS 驱动的肺中经常发生突变腺癌。我们在人类肺癌细胞系中的工作支持 STK11 丢失依赖性转录诱导肿瘤细胞因子作为可能影响抗 PD-1 治疗耐药性的一种机制。具体来说， RNAseq 分析表明 Yes 相关蛋白 1 (YAP1) 和核因子 Kappa B (NFkB) 被激活转录网络在 STK11 丢失时发生。 YAP1 是 HIPPO 信号轴中的最终效应器，发育过程中调节器官大小的关键途径。虽然 YAP1 之前已与 STK11 调节肿瘤细胞因子的表达，但其活性是否直接受 STK11 调节尚未确定。 NFkB 是调节多种细胞因子所必需的主转录因子，但与 YAP1 一样，STK11 如何调节 NFkB 活性的机制仍未得到解决。我们假设 STK11 缺失导致抗 PD-1 治疗通过改变肿瘤细胞因子来改变免疫细胞向肿瘤微环境的募集来产生耐药性发信号。我们提出的工作计划旨在表征诱导型免疫细胞招募的差异作为 STK11 状态和肿瘤转录组函数的肺癌小鼠模型。我们将利用免疫具有能力的基因工程小鼠，可发育出诱导型 KRAS 驱动或 KRAS/STK11 LoF 肺腺癌直接表征肿瘤基因型、肿瘤转录组和肿瘤之间的相关性差异性免疫细胞募集。然后，我们将利用该模型来评估逆转抗 PD-1 的策略治疗抵抗。具体来说，我们将评估下游的拮抗候选转录网络 STK11缺失，包括YAP1和NFkB，作为恢复抗肿瘤免疫微环境的策略，潜在地挽救 STK11 缺失肿瘤中的抗 PD1 功效。为了实现这一目标，我们将定义与仅由 KRAS 驱动的肿瘤相比，我们的小鼠表现出 STK11 依赖性抗 PD-1 耐药性。我们然后将评估拮抗候选网络是否逆转 STK11-LoF 转录表型，进而恢复 STK11 WT 肿瘤中观察到的免疫细胞补充。