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

项目摘要 肺癌是世界范围内癌症相关死亡的主要原因，并且在从不吸烟者中肺癌仍然是最常见的。 是最致命的癌症之一大约25%的肺癌由突变激活的KRAS驱动。一 治疗肺癌的主要障碍是对当前治疗性治疗的抗性。最近，第一种抑制剂 sotorasib被FDA批准用于患有KRASG 12 C驱动的肺癌的患者子集， 原发性和后天性耐药性正在上升。目前，该领域缺乏对如何 KRASG 12 C驱动的肺癌细胞在靶向治疗后存活以及如何克服 这个已知癌细胞可以上调自噬信号传导，这是一种营养清除剂途径， 细胞压力，如靶向治疗。以前的工作强调了基因沉默对基因表达的影响。 KRAS驱动的肺癌中的必需自噬基因Atg 5和Atg 7。我们试图测试 KRASG 12 C及其下游信号传导效应物对自噬信号传导和肺的药理学抑制 在KRASG 12 C驱动的肺癌模型中的肿瘤发生。我们假设KRASG 12 C驱动的肺癌细胞 用KRASG 12 C抑制剂处理和与选择性自噬共同处理后增加自噬通量 抑制剂将导致上级延迟的肿瘤生长。约30%的肺癌患者存在KRAS突变 还在LKB 1中具有缺失或失活突变，LKB 1是一种参与调节营养感测的蛋白质， 自噬LKB 1表达缺失的KRAS突变型肺癌患者的特征是侵袭性的， 行为和对标准治疗的抵抗。在其他KRAS驱动的癌症中，LKB 1-AMPK-ULK 1信号传导 轴是关于KRAS途径抑制后自噬通量如何增加的建议机制。 初步数据表明，在KRAS中抑制KRASG 12 C后，LKB 1与自噬通量的增加无关。 LKB 1表达缺失的突变型肺癌细胞。我们试图测试LKB 1是否是自噬所必需的 在KRASG 1/2C驱动的肺癌中的信号传导以及ULK 1/2激酶是否独立于LKB 1激活自噬。 为了测试这一点，我们将使用KRASG 12 C驱动的肺癌的新型鼠模型（KrasG 12 C-LSL）和人细胞系 模型该研究积累的结果将带来进一步的发现，从而改善人们的健康 肺癌患者，包括延长诊断后的平均寿命。

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.