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.

项目摘要肺癌既普遍又致命，强调需要继续研究和治疗发展。免疫治疗技术的进展，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表现出了很大的希望。不幸的是，不是全部患者反应。最近的临床研究已将抗PD-1治疗性抗性与特定组合联系起来体肿瘤突变。值得注意的是，缺乏功能性STK11的KRAS驱动的肺腺癌患者预后较差，转移发生率增加以及对抗PD-1治疗的耐药性明显。为什么 STK11功能丧失（LOF）与对抗PD-1治疗的抗性相关。丝氨酸苏氨酸激酶11（STK11）编码在KRAS驱动的肺中经常突变的重要肿瘤抑制基因腺癌。我们在人类肺癌细胞系中的工作支持STK11-LOSS依赖性转录诱导肿瘤细胞因子是一种可能影响抗PD-1治疗耐药性的机制。具体来说， RNASEQ分析表明与YES相关蛋白1（YAP1）和核因子KAPPA B（NFKB）激活转录网络发生在STK11损失后。 Yap1是河马信号轴的最终效应器，A 在开发过程中调节器官尺寸至关重要的途径。虽然yap1以前已与调节肿瘤细胞因子的表达，其活性是否直接受STK11调节尚未确定。 NFKB是调节大量细胞因子必不可少的主转录因子，但与YAP1一样，STK11如何可能调节NFKB活动仍然没有解决。我们假设STK11损失导致抗PD-1治疗通过改变肿瘤细胞因子改变免疫细胞募集到肿瘤微环境来抗性信号。我们提出的工作计划旨在表征可诱导的差异免疫细胞募集肺癌的小鼠模型与STK11状态和肿瘤转录组的关系。我们将利用免疫力能干的，具有基因工程的小鼠，发展可诱导的KRAS驱动或KRAS/STK11 LOF肺腺癌直接表征肿瘤基因型，肿瘤转录组和差异免疫细胞募集。然后，我们将利用此模型评估逆转抗PD-1的策略治疗抗性。具体而言，我们将评估下游的拮抗候选候选转录网络 STK11损失，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无肿瘤中的抗PD1疗效。为此，我们将定义与仅KRAS驱动的肿瘤相比，我们的小鼠表现出的STK11依赖性抗PD-1抗性。我们然后将评估对抗候选网络是否逆转STK11-LOF转录表型，进而恢复在STK11 WT肿瘤中观察到的免疫细胞补充。