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

探究突变 KRAS 等位基因失衡和共突变基因在 NSCLC 靶向治疗反应中的作用

• 批准号: 10672963
• 负责人: Bianca Diaz
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-09 至 2025-08-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672963
• 关键词: Affect; Aftercare; Alleles; Allelic Imbalance; Apoptosis; Binding; Biology; CDKN2A gene; CRISPR library; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Nucleus; Cells; Cessation of life; Clinic; Clinical; Clinical Management; Clustered Regularly Interspaced Short Palindromic Repeats; Codon Nucleotides; Combined Modality Therapy; Data; Development; Diagnosis; Disease; EGFR inhibition; Environment; Epidermal Growth Factor Receptor; Evaluation; Failure; Farnesyl Transferase Inhibitor; Future; GTP Binding; Genes; Genetic; Genetic Determinism; Genotype; Guanosine Triphosphate Phosphohydrolases; Human; Immune checkpoint inhibitor; Immunophenotyping; KRAS oncogenesis; KRAS2 gene; Knock-out; Libraries; Lung Adenocarcinoma; Lung Neoplasms; MAP Kinase Gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modeling; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Organoids; Outcome; Pancreas; Pathway interactions; Patients; Persons; Pharmacotherapy; Prognosis; Proliferating; Proliferation Marker; Resistance; Role; STK11 gene; Series; Signal Pathway; Signal Transduction; Silent Mutation; TP53 gene; Technology; Testing; Therapeutic; Toxic effect; Tumor Burden; Tumor Promotion; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; cancer type; cell growth; chemotherapy; clinically relevant; cohort; early phase clinical trial; extracellular; gain of function; genetic approach; genome editing; immune cell infiltrate; improved; in vivo; in vivo Model; inhibitor; loss of function; loss of function mutation; lung tumorigenesis; mouse model; mutant; mutant mouse model; novel therapeutics; pre-clinical; predictive marker; prevent; resistance mechanism; response; standard of care; targeted treatment; therapeutically effective; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; vector

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.

项目概要 每年有近200万人被诊断出患有肺癌，肺癌是癌症的主要原因 全球相关死亡。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成为 一个有前途的选择。 NSCLC 最常见的致癌驱动因素是 EGFR 和 KRAS 突变， 上调无数促进肿瘤细胞生长的下游信号通路。直到最近，努力 开发直接靶向 EGFR 或 KRAS 的疗法大部分都以失败告终。具体来说， 法尼基转移酶抑制剂和 MEK 和 RAF 等下游途径抑制剂的开发尚未 临床上显示生存率有所改善，并描述了耐药机制。的发现 KRASG12C 突变抑制剂（如 AMG 510 和 MRTX849）令人鼓舞，因为它们都显示出良好的前景 临床活性的迹象并有望改变 KRAS 突变癌症的治疗方法。这些抑制剂的工作原理是 与反应性 Cys12 共价结合，将 KRAS 锁定在其非活性 GDP 结合状态。然而，正如 以前的靶向治疗，耐药机制开始被描述。 利用小鼠的精确模型，我将检验 KRAS 等位基因失衡和遗传的假设 NSCLC 中的决定因素驱动肿瘤进展并对靶向治疗产生独特的反应。自从我们的 实验室开发了 LSL-Kras 等位基因系列，可以选择性靶向 WT Kras 等位基因，在目标 1 中，我将 使用基于 CRISPR 的基因组编辑技术在体内敲除 WT Kras 并测量对肿瘤的影响 负荷和 G12C 抑制剂反应。此外，我的目标是了解 WT KRAS 信号如何促进 肿瘤免疫微环境及其如何影响靶向治疗反应。在目标 2 中，我将使用一名患者 数据引导方法阐明肿瘤抑制因子的协同突变如何影响肿瘤进展 和 G12C 抑制剂反应。这种强大的遗传方法将使我能够直接询问 KRASG12C靶向治疗可能受到影响。确定破坏 KRASG12C 突变体的有效方法 NSCLC将对这些患者的临床管理产生深远的影响。因此，我们相信我们的工作 将为开发安全有效的非小细胞肺癌靶向疗法提供重要的临床前数据 其他癌症类型。