HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.

癌症是全球范围内导致死亡的主要原因。肝细胞生长因子（HGF）/MET酪氨酸激酶受体[MET、c-MET、肝细胞生长因子受体]通路激活与多种癌症特征的出现相关联。HGF/MET通路已成为多种实体瘤中重要的可干预靶点；因此，生物标志物的发现对于指导临床干预和患者分层，以实现个性化医疗的目标变得至关重要。本综述的重点在于探讨肿瘤组织或循环中HGF/MET通路异常激活如何提供诊断和预后生物标志物，以及药物反应预测生物标志物。许多荟萃分析表明，肿瘤组织中MET通路异常激活，包括MET基因过表达、基因扩增、外显子14跳跃和其他激活突变，几乎总是与生存期缩短和不良预后相关。大多数荟萃分析都是在非小细胞肺癌（NSCLC）、乳腺癌、头颈癌以及结直肠癌、胃癌、胰腺癌和其他胃肠道癌症中进行的。此外，多项研究表明，MET生物标志物在识别从HGF/MET靶向治疗（包括单药或联合用药）中获益最大的患者方面具有预测价值。在肾癌中对foretinib和savolitinib的响应、在NSCLC和结直肠癌中对tivantinib的响应显示出最高的预测价值。然而，一些基于MET表达的研究，尤其是那些在免疫组化评分系统中缺乏标准化方法或缺乏癌细胞对MET通路癌基因依赖性的研究，未能显示出在这些分层中的显著价值。扩增和突变异常的测量不太可能受到这些缺陷的影响。循环中MET可溶性外胚层（sMET）水平的增加也与不良预后相关；然而，与基于组织的生物标志物相比，证据并不那么充分。作为诊断生物标志物，sMET在前列腺癌、膀胱癌和黑色素瘤中区分癌症患者与健康个体方面已显示出其价值。另一方面，循环中HGF也被提出作为许多癌症中的有价值预后和诊断生物标志物；然而，关于HGF作为生物标志物的预测价值存在争议。其他生物标志物，如循环肿瘤DNA（ctDNA）和肿瘤HGF水平，也简要进行了介绍。总之，HGF/MET异常可以作为有价值的诊断、预后和预测生物标志物，并代表个性化癌症治疗的重要资产。