Resistance and Sensitivity to MET Inhibitors in Lung Cancer

项目总结 基因定向治疗是晚期非小细胞肺癌患者的标准治疗方案 (NSCLC)。对于晚期表皮生长因子受体(EGFR)突变的间变性淋巴瘤患者 激酶(ALK)或ROS1重排的非小细胞肺癌，酪氨酸激酶抑制剂(TKIs)是初始护理的标准 系统性治疗。然而，并不是所有的非小细胞肺癌患者都存在有针对性的基因组改变，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是一种跨膜的 受体酪氨酸激酶与恶性肿瘤的各个方面有关，包括肿瘤的生长、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)不依赖于MET信号的激活，包括突变、拷贝数增加和 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信号的策略，如TKI，靶向MET受体或HGF的抗体，已经被 已开发并正在进行临床评估。几种临床治疗肺癌靶点的方法 由于根据矛盾的生物标记物(MET)选择患者而不成功 免疫组织化学(IHC)；MetMab)或使用后来被发现不符合的试剂 抑制剂(替万替尼(ARQ 197))，MET中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突变体NSCLC中，MET扩增是获得性的一种机制 对EGFR TKIs的抵抗以及EGFR和MET的联合治疗是一种有效的治疗方法 为这类患者提供治疗方法。从头开始MET扩增和MET外显子14跳过突变已出现为 预测单药MET抑制剂临床疗效的基因组改变。耐人寻味的是，一些EGFR 突变的MET扩增的癌症也对单一的MET抑制有反应。这样做的机制基础是 未知。在这些不同的MET改变群体中，MET外显子14突变是最常见的(约3% 所有肺腺癌)和多个临床试验目前正在评估单剂MET TKIs MET外显子14突变型NSCLC。然而，尽管MET TKI在此类癌症中具有临床疗效，但获得性 阻力将不可避免地发展起来。因此，我们计划研究获得性抗药性的机制。 MET靶向治疗，并确定耐药癌症是否保持对MET的依赖。这个 对获得性耐药性的机械性理解可能有助于确定替代方案是否符合 抑制物(在存在次级MET突变的情况下)或组合(针对平行或下游 信号通路)很可能在治疗上有效。我们正在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：至 了解平行或下游通路激活如何导致MET抑制剂耐药性；目标3： 确定单药MET抑制剂在EGFR突变肿瘤中的敏感性机制。

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.