Interrogating the role of mutant KRAS allelic imbalance and co-mutated genes in targeted therapy response of NSCLC

项目总结 每年有近200万人被诊断出患有肺癌，是导致癌症的主要原因。 全球范围内的相关死亡。非小细胞肺癌(NSCLC)患者的护理标准变化不大 然而，在过去的几年里，靶向治疗和免疫检查点抑制剂最近已经成为 一个很有希望的选择。NSCLC中最常见的致癌驱动因素是EGFR和KRAS突变，其中 上调促进肿瘤细胞生长的无数下游信号通路。直到最近，人们还在努力 开发直接针对EGFR或KRAS的疗法在很大程度上失败了。具体来说， 法尼基转移酶抑制剂和下游途径抑制剂如MEK和RAF的开发还没有 在临床上显示存活率的改善和耐药机制被描述。发现了 AMG 510和MRTX849等KRASG12C突变抑制剂令人鼓舞，因为它们都显示出很有希望 临床活动的迹象，并有望改变KRAS突变癌症的治疗。这些抑制剂的作用方式是 共价结合到反应性的Cys12，将KRAS锁定在其非活性的GDP结合状态。然而，就像在 以前的靶向治疗、耐药机制开始被描述。 利用小鼠的精确建模，我将检验KRAS等位基因失衡和遗传 NSCLC中的决定因素推动肿瘤进展，并对靶向治疗产生独特的反应。因为我们的 实验室已经开发出LSL-Kras等位基因系列，允许选择性靶向WT Kras等位基因，在目标1中，我将 利用基于CRISPR的基因组编辑技术在体内敲除WT Kras并测量其在肿瘤中的作用 负荷和G12C抑制反应。此外，我的目标是了解WT KRAS信号如何有助于 肿瘤免疫微环境及其如何影响靶向治疗反应。在《目标2》中，我会用一个病人 数据引导的方法阐明肿瘤抑制基因的协同突变如何影响肿瘤进展 和G12C抑制反应。这种强大的遗传方法将使我能够直接询问 KRASG12C靶向治疗可能会受到影响。寻找破坏KRASG12C突变体的有效方法 非小细胞肺癌将对这些患者的临床治疗产生深远的影响。因此，我们相信我们的工作 将有助于开发安全有效的非小细胞肺癌和非小细胞肺癌靶向治疗 其他癌症类型。

PROJECT SUMMARY Nearly 2 million people are diagnosed with lung cancer each year and it is the leading cause in cancer related death worldwide. Standard of care for non-small cell lung cancer (NSCLC) patients has changed little over the past several years however targeted therapies and immune checkpoint inhibitors have recently become a promising option. The most common oncogenic drivers in NSCLC are mutations in EGFR and KRAS which upregulate a myriad of downstream signaling pathways that promote tumor cell growth. Until recently, efforts to develop therapeutics that directly target EGFR or KRAS have largely been met by failure. Specifically, development of farnesyl transferase inhibitors and downstream pathway inhibitors like MEK and RAF, have not shown improvement in survival in the clinic and resistance mechanisms are described. The discovery of KRASG12C mutant inhibitors like AMG 510 and MRTX849 is encouraging as they have both shown promising signs of clinical activity and promise to transform treatment of KRAS mutant cancer. These inhibitors work by covalently binding to the reactive Cys12 locking KRAS in its inactive GDP-bound state. However, as with previously targeted therapies, mechanisms of resistance are beginning to be described. Utilizing precision modeling in mice, I will test the hypothesis that KRAS allelic imbalance and genetic determinants in NSCLC drive tumor progression and confer unique responses to targeted therapies. Since our lab has developed LSL-Kras allelic series that allows for selective targeting of the WT Kras allele, in Aim 1, I will use CRISPR-based genome editing technology to knockout WT Kras in vivo and measure effects in tumor burden and G12C inhibitor response. Further, I aim to understand how WT KRAS signaling contributes to the tumor immune microenvironment and how it affects targeted treatment response. In Aim 2, I will use a patient data guided approach to elucidate how cooperative mutations in tumor suppressors effect tumor progression and G12C inhibitor response. This powerful genetic approach will allow me to directly interrogate ways in which KRASG12C targeted therapy can be affected. Identifying an effective approach to disrupt KRASG12C mutant NSCLC will have a profound impact on the clinical management of these patients. Thus, we believe our work will contribute significant pre-clinical data to developing safe and effective targeted therapies for NSCLC and other cancer types.