Investigating KRAS Signaling and Autophagy Co-inhibition in KRAS-mutant Lung Cancer

研究 KRAS 突变肺癌中的 KRAS 信号传导和自噬共抑制

基本信息

批准号：
10600716
负责人：
Phaedra Ghazi
金额：
$ 3.41万
依托单位：
UNIVERSITY OF UTAH
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：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600716
关键词：
Aftercare Aggressive behavior Autophagocytosis Basic Science Biochemical Process CRISPR/Cas technology Cancer Etiology Cancer Model Cancer Patient Cancer cell line Cell Line Cell Survival Cell physiology Cells Cellular Stress Cessation of life Chimeric Proteins Clinical Clinical Trials Cytoprotection Data Dependence Diagnosis Disease Engineering Euthanasia FDA approved Flow Cytometry Future Genes Genetic Genetically Engineered Mouse Goals Human Human Cell Line Immunohistochemistry Investigation KRAS2 gene KRASG12D Longevity Lung Neoplasms MAP2K1 gene Malignant Neoplasms Malignant neoplasm of lung Measures Modeling Mus Mutate Mutation Nutrient Oncogenes Pathway interactions Patients Phosphorylation Phosphotransferases Pre-Clinical Model Process Proliferating Proteins Recycling Regulation Reporter Research Research Project Grants Resistance Role STK11 gene Signal Induction Signal Transduction Survival Rate Testing Therapeutic Therapeutic Intervention Translating Tumor Burden United States Up-Regulation Western Blotting Woman Work X-Ray Computed Tomography Xenograft procedure cancer cell cytotoxic detection of nutrient fluorescence imaging improved inhibition of autophagy inhibitor lung cancer cell lung carcinogenesis lung health lung lesion lung tumorigenesis men microCT mouse model mutant never smoker novel patient response patient subsets pharmacologic predictive marker resistance mechanism response standard care targeted treatment therapeutic target therapeutically effective therapy outcome therapy resistant treatment response tumor tumor growth tumor initiation tumor xenograft

项目摘要

PROJECT ABSTRACT Lung cancer is the leading cause of cancer related deaths worldwide and lung cancer in never smokers is still among the top fatal cancers. Approximately 25% of lung cancers are driven by mutationally activated KRAS. A major obstacle in treating lung cancer is resistance to current therapeutic treatments. Recently, the first inhibitor of KRASG12C, sotorasib, was approved by the FDA for a subset of patients with KRASG12C driven lung cancer but primary and acquired resistance is arising. Currently, the field lacks a comprehensive understanding of how KRASG12C driven lung cancer cells survive after treatment with targeted therapy and how to overcome this. It is known that cancer cells can upregulate autophagy signaling, a nutrient scavenger pathway, in response to cellular stresses such as targeted therapy. Previous work has highlighted the impact of genetic silencing of essential autophagy genes Atg5 and Atg7 in KRAS driven lung cancer. We seek to test the impact of pharmacological inhibition of KRASG12C and its downstream signaling effectors on autophagy signaling and lung tumorigenesis in KRASG12C driven lung cancer models. We hypothesize that KRASG12C driven lung cancer cells increase autophagic flux after treatment with KRASG12C inhibitors and co-treatment with selective autophagy inhibitors will lead to superior delayed tumor growth. About 30% of lung cancer patients with KRAS mutations also have a deletions or inactivating mutations in LKB1, a protein involved in regulation of nutrient sensing and autophagy. KRAS-mutant lung cancer patients with loss of LKB1 expression are characterized by an aggressive behavior and resistance to standard treatment. In other KRAS-driven cancers, the LKB1-AMPK-ULK1 signaling axis is the proposed mechanism as to how autophagic flux increases following KRAS pathway inhibition. Preliminary data suggests LKB1 is dispensable for increases in autophagy flux after KRASG12C inhibition in KRAS mutant lung cancer cells with loss of LKB1 expression. We seek to test if LKB1 is necessary for autophagy signaling in KRASG12C driven lung cancer and if the ULK1/2 kinases activates autophagy independently of LKB1. To test this, we will use a novel murine model of KRASG12C driven lung cancer (KrasG12C-LSL) and human cell line models. Results accumulated from the study will lead to further findings that in turn will improve the health of lung cancer patients, including expanding the average life span after diagnosis.

项目摘要肺癌是全球癌症与癌症相关的主要原因，而从未吸烟的肺癌仍然是在最大的致命癌症中。大约25％的肺癌是由突变激活的KRA驱动的。一个治疗肺癌的主要障碍是对当前治疗治疗的抗性。最近，第一个抑制剂 sotorasib的Krasg12c，FDA批准了Krasg12c驱动的肺癌的一部分，但主要和获得的阻力正在产生。目前，该领域对如何 KRASG12C驱动的肺癌细胞在用靶向治疗治疗后生存以及如何克服这。众所周知，癌细胞可以上调自噬信号传导，这是一种营养清除途径到诸如靶向治疗之类的细胞应激。以前的工作强调了遗传沉默的影响 KRAS驱动的肺癌中必需的自噬基因ATG5和ATG7。我们试图测试 KRASG12C的药理抑制及其下游信号传导效应子对自噬信号和肺的抑制 KRASG12C驱动的肺癌模型中的肿瘤发生。我们假设KRASG12C驱动的肺癌细胞用KRASG12C抑制剂治疗后增加自噬通量并与选择性自噬进行共同治疗抑制剂将导致肿瘤的延迟生长。大约30％的肺癌患者患有KRAS突变 LKB1中还具有缺失或灭活突变，这是一种参与养分感应和的蛋白质自噬。 LKB1表达丧失的KRAS突变肺癌患者的特征是侵略性行为和抵抗标准治疗。在其他KRAS驱动的癌症中，LKB1-AMPK-ULK1信号传导轴是针对KRAS途径抑制后自噬通量如何增加的提议机制。初步数据表明，LKB1对于KRAS抑制KRASG12C后自噬通量的增加是不可取的突变的肺癌细胞，失去LKB1表达。我们试图测试LKB1是否需要自噬需要 KRASG12C驱动的肺癌和ULK1/2激酶在KRASG12C中的信号传导独立于LKB1激活自噬。为了测试这一点，我们将使用Krasg12c驱动的肺癌（KRASG12C-LSL）和人类细胞系的新型鼠模型型号。从研究中积累的结果将导致进一步的发现，进而将改善肺癌患者，包括扩大诊断后的平均寿命。