Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors.

针对 LKB1 突变肿瘤的新治疗漏洞。

• 批准号: 10443802
• 负责人: NABEEL El-BARDEESY
• 金额: $ 66.39万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443802
• 关键词: 3-Dimensional; Antigen Presentation; Biological Assay; Biopsy; Blood; Cancer Patient; Carbon; Cell Death; Cell Line; Cell Survival; Cells; Cellular Metabolic Process; Clinical Trials; Combined Modality Therapy; Coupled; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Modification Methylases; Data; Development; Elements; Enrollment; Epithelial Cells; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Glucose; Glycine; Human; Hypersensitivity; Immune; Immune checkpoint inhibitor; Immune response; Immunologic Markers; Immunologic Surveillance; Immunologics; Immunotherapy; Interferon Type I; Interferons; KRAS2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Metabolism; Microfluidics; Modeling; Molecular; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Nutrient; Oncogenic; Outcome; PDL1 inhibitors; Pancreatic Ductal Adenocarcinoma; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Point Mutation; Production; Protein-Serine-Threonine Kinases; Research Personnel; Retrotransposon; Role; S-Adenosylmethionine; STK11 gene; Sampling; Science; Serine; Signal Transduction; Specimen; System; T cell response; Testing; Therapeutic; Tissues; Transcript; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Viral; Vulnerable Populations; Xenograft procedure; anti-PD-L1 antibodies; behavioral response; cancer type; cell growth; checkpoint inhibition; clinical translation; cohort; cytokine; cytotoxic; demethylation; detection of nutrient; epigenetic regulation; in vivo; inhibitor; molecular marker; mutant; neoplastic cell; new therapeutic target; novel; novel therapeutics; pancreatic ductal adenocarcinoma cell; phase 1 study; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; programs; response; single-cell RNA sequencing; standard of care; synergism; translational approach; treatment strategy; tumor; tumor behavior; tumor microenvironment; tumor-immune system interactions; tumorigenesis

KRAS is the most frequently mutated gene in human cancers. Unfortunately, KRAS inhibitors have been elusive and attempts to target downstream signaling have had limited benefit. KRAS mutations are particularly common in two especially deadly cancers: non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDA). The basis for this multiple investigator R01 is our recent identification of a distinct molecular program in a genetically defined subset of KRAS mutant tumors—specifically those with concurrent KRAS/LKB1 mutations— that points to a novel therapeutic vulnerability. The LKB1/STK11 tumor suppressor encodes a serine-threonine kinase that integrates nutrient availability, cell metabolism, and cell growth. We recently discovered that KRAS activation and LKB1 loss synergize to drive tumorigenesis associated with pronounced rewiring of metabolism that is coupled to changes in epigenetic regulation. In particular, we find that oncogenic cooperation between these mutations is fueled by pronounced induction of the serine-glycine- one carbon network coupled to generation of the methyl donor S-adenosylmethionine. In concert, DNA methyltransferases (DNMTs) are upregulated, leading to increased DNA methylation, with particular enrichment at retrotransposon elements, which are consequently silenced. Accordingly, KRAS-LKB1 mutant NSCLC and PDA cell lines, xenografts, and GEMMs are highly sensitive to DNMT inhibitors (DNMTi), compared to equivalent cancers lacking LKB1 mutations. Importantly, we show that this sensitivity is associated with pronounced activation of retrotransposons and induction of the interferon (IFN)-mediated cytotoxic response. IFN signaling also alters immune surveillance, both positively by increasing antigen presentation, and negatively by upregulating PD-L1. Thus, combined immune checkpoint inhibition and DNMTi represents a novel translational strategy for this vulnerable group of patients. Our proposal seeks to dissect the differences in immune microenvironment and molecular circuitry of genetically defined NSCLC and PDA subsets and to investigate the efficacy and mechanisms of response to combination therapy. These studies will utilize both human tumors and GEMMs to further define the role of discrete genetic alterations in conferring this therapeutic vulnerability. Importantly, our data has also led to the development of an investigator-initiated Phase I study of a DNMTi and an immune checkpoint inhibitor in KRAS/LKB1 NSCLC with expansion planned for PDA. Assessment of on-study specimens will be integrated with other analyses described here to further extend the clinical translation of this therapeutic approach for patients whose options are otherwise limited.

KRAS是人类癌症中最常见的突变基因。不幸的是，KRAS抑制剂已经 难以实现，并且靶向下游信号传导的尝试具有有限的益处。KRAS突变尤其 常见于两种特别致命的癌症：非小细胞肺癌（NSCLC）和胰腺导管癌。 腺癌（PDA）。这个多研究者R 01的基础是我们最近发现的一种独特的 在基因定义的KRAS突变肿瘤亚组中的分子程序-特别是那些并发 KRAS/LKB 1突变-这表明了一种新的治疗弱点。LKB 1/STK 11肿瘤抑制因子 编码丝氨酸-苏氨酸激酶，其整合营养物质利用、细胞代谢和细胞生长。我们 最近发现，KRAS激活和LKB 1丢失协同作用，推动与肿瘤相关的肿瘤发生。 代谢的明显重新布线，与表观遗传调节的变化相关联。特别是，我们发现 这些突变之间的致癌合作是由丝氨酸-甘氨酸- 一个碳网络与甲基供体S-腺苷甲硫氨酸的产生偶联。在音乐会上，DNA 甲基转移酶（DNMT）上调，导致DNA甲基化增加，特别是 在逆转录转座子元件富集，其因此被沉默。因此，KRAS-LKB 1突变体 NSCLC和PDA细胞系、异种移植物和GEMM对DNMT抑制剂（DNMTi）高度敏感， 与缺乏LKB 1突变的同等癌症相比。重要的是，我们表明，这种敏感性是 与逆转录转座子的显著激活和干扰素（IFN）介导的诱导相关 细胞毒性反应IFN信号也改变免疫监视，两者都是通过增加抗原 通过上调PD-L1表达而呈负性。因此，联合免疫检查点抑制和DNMTi 代表了针对这一弱势患者群体的一种新的翻译策略。我们的建议旨在剖析 遗传定义的NSCLC和PDA的免疫微环境和分子电路的差异 亚群，并研究联合治疗的疗效和机制。这些研究将 利用人类肿瘤和GEMM来进一步定义离散遗传改变在赋予这种功能中的作用。 治疗脆弱性。重要的是，我们的数据还导致了一种由计算机启动的 DNMTi和免疫检查点抑制剂在KRAS/LKB 1 NSCLC中的I期研究，计划进行扩展 对于PDA。研究期间标本的评估将与此处描述的其他分析整合，以进一步 扩大这种治疗方法的临床转化，以帮助那些选择有限的患者。