Resistance and Sensitivity to MET Inhibitors in Lung Cancer

肺癌对 MET 抑制剂的耐药性和敏感性

基本信息

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
项目类别：
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

项目摘要

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.

项目概要基因型定向治疗是晚期非小细胞肺癌患者的标准治疗（非小细胞肺癌）。对于患有晚期表皮生长因子受体（EGFR）突变、间变性淋巴瘤的患者激酶 (ALK) 或 ROS1 重排 NSCLC，酪氨酸激酶抑制剂 (TKI) 是初始护理标准全身疗法。然而，并非所有 NSCLC 患者都存在可靶向的基因组改变，甚至在那些最初可以用 TKI 治疗的患者，不可避免地会产生获得性耐药性。 MET是一种跨膜物质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、存活、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）独立激活 MET 信号传导，包括突变、拷贝数增益和在包括肺癌在内的许多恶性肿瘤中都观察到了重排。几种治疗方法抑制 MET 信号传导的策略，例如 TKI、针对 MET 受体或 HGF 的抗体，已被已开发并正在进行临床评估。作为肺癌靶向 MET 的几种临床方法由于根据矛盾的生物标志物（MET 免疫组织化学（IHC）； METMab）或使用随后被发现不是真正 MET 的试剂抑制剂（Tivantinib (ARQ 197)），MET 的基因组改变已被证明是更可靠的预测因子 MET抑制剂的临床疗效。在 EGFR 突变型 NSCLC 中，MET 扩增是获得性突变的一种机制对 EGFR TKI 耐药，EGFR 和 MET 联合靶向治疗是一种有效的治疗方法针对此类患者的方法。从头 MET 扩增和 MET 外显子 14 跳跃突变已出现预测单药 MET 抑制剂临床疗效的基因组改变。有趣的是，一些 EGFR 突变型 MET 扩增癌症也对单药 MET 抑制有反应。其机制基础是未知。在这些不同的 MET 改变人群中，MET 外显子 14 突变是最常见的（约 3%）所有肺腺癌），目前正在进行多项评估单药 MET TKI 的临床试验 MET 外显子 14 突变非小细胞肺癌。然而，尽管 MET TKI 在此类癌症中具有临床疗效，但抵抗必然会发展。因此，我们计划研究获得性耐药的机制 MET 靶向治疗并确定耐药癌症是否保留其 MET 依赖性。这对获得性耐药性的机制理解可能有助于确定是否有替代的 MET 抑制剂（在存在二次 MET 突变的情况下）或组合（针对平行或下游信号通路）可能具有治疗效果。我们通过以下方式实现这一目标具体目标：目标 1：确定 MET 突变对 MET 抑制剂疗效的影响；目标 2：了解并行或下游途径激活如何导致 MET 抑制剂耐药性；目标 3：确定单药 MET 抑制剂对 EGFR 突变癌症的敏感性机制。