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: 10333326
• 负责人: Pasi A Janne
• 金额: $ 38.26万
• 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/10333326
• 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; 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 基因型导向治疗是晚期非小细胞肺癌患者的标准治疗 （NSCLC）。对于晚期表皮生长因子受体（EGFR）突变、间变性淋巴瘤患者 对于ALK或ROS 1重排的NSCLC，酪氨酸激酶抑制剂（TKI）是初始标准治疗 全身治疗。然而，并非所有NSCLC患者都具有靶向基因组改变，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 受体酪氨酸激酶参与恶性肿瘤的各个方面，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）独立的MET信号传导的激活，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已经观察到重排。几种治疗 抑制MET信号传导的策略，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。作为靶向MET治疗肺癌的几种临床方法， 由于基于矛盾的生物标志物（MET）选择患者， 免疫组织化学（IHC; METMab）或使用随后发现不是真正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NSCLC的一种机制。 EGFR TKI耐药，EGFR和MET联合治疗是一种有效的治疗方法 对于这样的患者。新生MET扩增和MET外显子14跳跃突变已经出现， 预测单药MET抑制剂临床疗效的基因组改变。有趣的是， 突变MET扩增的癌症也响应于单一药剂MET抑制。其机械基础是 未知在这些不同的MET改变的人群中，MET外显子14突变是最常见的（约3%）。 所有肺腺癌），目前正在进行多项临床试验，评价单药MET TKI 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， 阻力将不可避免地产生。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。的 对获得性耐药机制的理解可能有助于确定替代MET 抑制剂（在存在次级MET突变的情况下）或组合（靶向平行或下游突变）。 信号通路）可能是治疗有效的。我们通过以下方式实现这一目标： 具体目的：目的1：确定MET突变对MET抑制剂疗效的影响;目的2： 了解平行或下游途径激活如何导致MET抑制剂耐药;目标3： 确定EGFR突变型癌症中单药MET抑制剂敏感性的机制。

项目成果

Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.

• DOI: 10.1158/1535-7163.mct-21-0344
• 发表时间: 2022-03
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Bahcall M;Paweletz CP;Kuang Y;Taus LJ;Sim T;Kim ND;Dholakia KH;Lau CJ;Gokhale PC;Chopade PR;Hong F;Wei Z;Köhler J;Kirschmeier PT;Guo J;Guo S;Wang S;Jänne PA
• 通讯作者: Jänne PA

Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer.

• DOI: 10.1158/1078-0432.ccr-18-0876
• 发表时间: 2018-12-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Bahcall M;Awad MM;Sholl LM;Wilson FH;Xu M;Wang S;Palakurthi S;Choi J;Ivanova EV;Leonardi GC;Ulrich BC;Paweletz CP;Kirschmeier PT;Watanabe M;Baba H;Nishino M;Nagy RJ;Lanman RB;Capelletti M;Chambers ES;Redig AJ;VanderLaan PA;Costa DB;Imamura Y;Jänne PA
• 通讯作者: Jänne PA

Targeting MET Dysregulation in Cancer.

• DOI: 10.1158/2159-8290.cd-19-1446
• 发表时间: 2020-07
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Recondo G;Che J;Jänne PA;Awad MM
• 通讯作者: Awad MM