Resistance and Sensitivity to MET Inhibitors in Lung Cancer

肺癌对 MET 抑制剂的耐药性和敏感性

• 批准号: 10079475
• 负责人: Pasi A Janne
• 金额: $ 39.04万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079475
• 关键词: Antibodies; Biological Markers; Cancer Patient; Clinical; Clinical Trials; Combined Modality Therapy; Coupled; DNA Sequence Alteration; Dependence; Development; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exons; Genotype; HGF gene; Immunohistochemistry; In Vitro; KRAS2 gene; Lead; Ligands; Lung Adenocarcinoma; MET gene; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patient Care; Patients; Population; Pre-Clinical Model; ROS1 gene; Receptor Protein-Tyrosine Kinases; Resistance; Signal Pathway; Signal Transduction; Systemic Therapy; Therapeutic; Translating; Tyrosine Kinase Inhibitor; acquired drug resistance; anaplastic lymphoma kinase; angiogenesis; base; cell free DNA; clinical efficacy; clinical predictors; effective therapy; improved; in vivo; inhibitor/antagonist; migration; mutant; neoplastic cell; overexpression; pre-clinical; prevent; receptor; refractory cancer; research clinical testing; standard of care; targeted treatment; therapeutically effective; treatment strategy; tumor growth

PROJECT SUMMARY Genotype directed therapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). For patients with advanced epidermal growth factor receptor (EGFR) mutant, anaplastic lymphoma kinase (ALK) or ROS1 rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are the standard of care initial systemic therapies. However, not all NSCLC patients harbor a targetable genomic alteration and even among those that can be initially treated with a TKI, acquired resistance inevitably develops. MET is a transmembrane receptor tyrosine kinase implicated in various aspects of malignancy including tumor growth, survival, invasion, migration, angiogenesis and metastasis. Aberrant alterations in the MET gene, leading to ligand (hepatocyte growth factor; HGF) independent activation of MET signaling, including mutations, copy number gains and rearrangements have been observed in many malignancies including in lung cancers. Several therapeutic strategies to inhibit MET signaling such as TKIs, antibodies targeting the MET receptor or HGF, have been developed and are undergoing clinical evaluation. As several clinical approaches to target MET in lung cancer have been unsuccessful as a result of selecting patients based on an ambivalent biomarker (MET immunohistochemistry (IHC); METMab) or using agents that were subsequently discovered not to be true MET inhibitors (Tivantinib (ARQ 197)), genomic alterations in MET have proven to be more reliable predictors of the clinical efficacy of MET inhibitors. In EGFR mutant NSCLC, MET amplification is a mechanism of acquired resistance to EGFR TKIs and the combination of EGFR and MET directed therapies is an effective therapeutic approach for such patients. De novo MET amplification and MET exon 14 skipping mutations have emerged as genomic alterations that predict for the clinical efficacy of single agent MET inhibitors. Intriguingly, some EGFR mutant MET amplified cancers also respond to single agent MET inhibition. The mechanistic basis for this is unknown. Of these different MET altered populations, MET exon 14 mutations are the most common (~ 3% of all lung adenocarcinomas) and multiple clinical trials are currently underway evaluating single agent MET TKIs in MET exon 14 mutant NSCLC. However, despite the clinical efficacy of MET TKIs in such cancers, acquired resistance will inevitably develop. Accordingly, we plan to investigate the mechanisms of acquired resistance to MET targeted therapies and determine whether drug resistant cancers retain their MET dependency. The mechanistic understanding of acquired drug resistance may help determine whether an alternative MET inhibitor (in the presence of a secondary MET mutation) or a combination (targeting a parallel or downstream signaling pathway) is likely to be therapeutically effective. We are accomplishing this through the following specific aims: Aim 1: To determine impact of MET mutations on efficacy of MET inhibitors; Aim 2: To understand how parallel or downstream pathway activation leads to MET inhibitor resistance; Aim 3:To determine mechanism of single agent MET inhibitor sensitivity in EGFR mutant cancers.

项目摘要 基因型定向治疗是晚期非小细胞肺癌患者的护理标准 （NSCLC）。对于表皮晚期生长因子受体（EGFR）突变体的患者，变性淋巴瘤 激酶（ALK）或ROS1重新排列的NSCLC，酪氨酸激酶抑制剂（TKI）是护理标准初始 系统性疗法。但是，并非所有NSCLC患者都具有目标的基因组改变，甚至在 那些最初可以用TKI治疗的人不可避免地会发展出来。 MET是跨膜 受体酪氨酸激酶与恶性肿瘤的各个方面有关，包括肿瘤生长，生存，侵袭， 迁移，血管生成和转移。 MET基因的异常改变，导致配体（肝细胞 生长因子； HGF）MET信号传导的独立激活，包括突变，拷贝数增长和 在包括肺癌在内的许多恶性肿瘤中都观察到重排。几种治疗性 抑制MET信号的策略，例如TKI，针对MET受体或HGF的抗体 开发并正在进行临床评估。随着肺癌中的几种临床靶标的临床方法 基于矛盾的生物标志物选择患者的结果是未能成功的 免疫组织化学（IHC）； metmab）或使用后来发现不为真实的代理 抑制剂（tivantinib（ARQ 197）），事实证明，MET的基因组改变是对该的更可靠的预测指标 MET抑制剂的临床功效。在EGFR突变NSCLC中，MET扩增是一种获得的机制 对EGFR TKI的耐药性以及EGFR和MET的定向疗法的组合是有效的治疗方法 此类患者的方法。从头遇到放大并满足外显子14跳过突变已出现 预测单药抑制剂的临床疗效的基因组改变。有趣的是，一些EGFR 突变体的放大癌症也对单药抑制作用做出反应。机械基础是 未知。在这些不同的MET改变的种群中，Met Exon 14突变是最常见的（〜3％的3％ 目前正在进行所有肺腺癌和多个临床试验的评估 在MET 14突变体NSCLC中。然而，尽管在这种癌症中获得了MET TKI的临床功效，但已获得 阻力将不可避免地发展。因此，我们计划研究获得的抗性机制 满足有针对性的疗法，并确定耐药性癌症是否保留其MET依赖性。这 对获得的耐药性的机械理解可能有助于确定替代性是否达到 抑制剂（在存在二次MET突变的情况下）或组合（靶向平行或下游 信号通路）可能在治疗上有效。我们正在通过以下 具体目的：目标1：确定MET突变对MET抑制剂功效的影响；目标2：到 了解平行或下游途径激活如何导致MET抑制剂抗性；目标3：到 确定EGFR突变体癌症中单药MET抑制剂敏感性的机制。