MET受体酪氨酸激酶（METex14）的外显子跳跃突变在癌症中越来越多见，并在非小细胞肺癌（NSCLC）中出现率为3-4％。仅有50％的患者对使用MET-酪氨酸激酶抑制剂（TKI）的治疗产生有益反应，因此有必要理解METex14致癌性和对TKI的敏感性的机制。METex14是否是驱动突变，以及在离体和离体功能范围内是否需要肝细胞生长因子（HGF）仍未从以前的临床前模型完全阐明。我们使用CRISPR / Cas9在非转化人肺细胞中开发了一个METex14 / WT等基因模型，并报告METex14单一变异足以驱动MET依赖型的体外无附着生存和运动以及体内肿瘤形成，使其对MET-TKI敏感。但是，我们也表明人类HGF（hHGF）是必需的，如使用了人性化HGF敲入小鼠株的体内演示，并在METex14 NSCLC患者样本的肿瘤细胞中进一步检测到。我们的结果还表明，在我们的细胞模型中，METex14致癌性不是逃逸降解的结果。因此，我们开发了一种有价值的临床前研究模型，并提出具有潜在临床意义的结果。本文受版权保护。保留所有权利。

Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3-4% of non-small cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET-tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in non-transformed human lung cells, and report that the METex14 single alteration was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET-TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanized HGF knock-in strain of mice and further detected in tumor cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication.This article is protected by copyright. All rights reserved.