Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors.

针对 LKB1 突变肿瘤的新治疗漏洞。

• 批准号: 10208803
• 负责人: NABEEL El-BARDEESY
• 金额: $ 67.74万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208803
• 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/antagonist; 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抑制剂已经被 难以捉摸的和针对下行信号的尝试带来的好处有限。KRAS突变特别是 常见于两种特别致命的癌症：非小细胞肺癌和胰腺导管 腺癌(PDA)。这多个调查者R01的基础是我们最近发现的一个不同的 在基因定义的KRAS突变肿瘤子集中的分子程序-特别是那些并发的 KRAS/LKB1突变--这表明了一种新的治疗脆弱性。LKB1/STK11抑癌基因 编码一种丝氨酸-苏氨酸激酶，它整合了营养供应、细胞新陈代谢和细胞生长。我们 最近发现，KRAS激活和LKB1丢失协同作用推动肿瘤的发生 伴随着表观遗传调控的变化而发生的新陈代谢的显著改变。特别是，我们发现 这些突变之间的致癌基因合作是通过显著诱导丝氨酸-甘氨酸- 一碳网络偶联生成的甲基供体S-腺苷蛋氨酸。在演唱会上，DNA 甲基转移酶(DNMT)上调，导致DNA甲基化增加，尤其是 在反转录转座子元件上的浓缩，从而使其沉默。相应地，KRAS-LKB1突变体 NSCLC和PDA细胞系、异种移植和GEMM对DNMT抑制剂(DNMTi)高度敏感， 与缺乏LKB1突变的同等癌症相比。重要的是，我们证明了这种敏感性是 与显著激活反转录转座子和诱导干扰素(干扰素)介导的 细胞毒性反应。干扰素信号也通过增加抗原来改变免疫监视。 呈现，并通过上调PD-L1负向调节。因此，结合免疫检查点抑制和DNMTi 为这一弱势群体的患者提供了一种新的翻译策略。我们的建议旨在剖析 遗传性非小细胞肺癌与PDA免疫微环境及分子回路的差异 并探讨联合治疗的疗效和机制。这些研究将 利用人类肿瘤和GEMM进一步确定离散基因改变在这方面的作用 治疗的脆弱性。重要的是，我们的数据还导致了一种由调查员发起的 计划扩大的KRAS/LKB1非小细胞肺癌DNMTi和免疫检查点抑制剂的I期研究 用于掌上电脑。对正在研究的标本的评估将与此处描述的其他分析相结合，以进一步 将这一治疗方法的临床翻译扩展到其他选择有限的患者。