Data from many preclinical studies, including those using cellular models of colorectal, gastric, gastro-oesophageal and gastro-oesophageal junction cancers, indicate that the hepatocyte growth factor (HGF)–hepatocyte growth factor receptor (c-MET) pathway is vital for the growth, survival and invasive potential of gastrointestinal cancers. Following the availability of data from these various studies, and data on c-MET expression as a biomarker that indicates a poor prognosis in patients with gastrointestinal cancer and increased c-MET expression, inhibitors targeting this pathway have entered the clinic in the past decade. However, the design of clinical trials that incorporate the use of HGF/c-MET inhibitors in their most appropriate genetic and molecular context remains crucial. Recognizing and responding to this challenge, the European Commission funded Framework 7 MErCuRIC programme is running a biomarker-enriched clinical trial investigating the efficacy of combined c-MET/MEK inhibition in patients with RAS-mutant or RAS-wild-type metastatic colorectal cancer with aberrant c-MET expression. The design of this trial enables the continued refinement of the predictive biomarker and co-development of companion diagnostics. In this Review, we focus on advances in our understanding of inhibition of the HGF/c-MET pathway in patients with gastro-intestinal cancers, the prominent challenges facing the clinical translation and implementation of agents targeting HGF/c-MET, and discuss the various efforts, and associated obstacles to the discovery and validation of biomarkers that will enable patient stratification in this context.

中文翻译：

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针对胃肠道肿瘤中的c-MET：原理，机遇和挑战

来自许多临床前研究的数据，包括那些使用结直肠癌，胃癌，胃食管癌和胃食管交界癌的细胞模型的研究，表明肝细胞生长因子（HGF）-肝细胞生长因子受体（c-MET）通路对于肝癌至关重要。胃肠道癌的生长，存活和侵袭潜能。在获得了来自这些各种研究的数据以及有关c-MET表达作为生物标志物的数据后，这些数据表明胃肠道癌症患者的预后较差且c-MET表达增加，靶向该途径的抑制剂在过去的十年中进入了临床。但是，在最合适的遗传和分子背景下结合使用HGF / c-MET抑制剂的临床试验设计仍然至关重要。认识到并应对这一挑战，具有异常c-MET表达的RAS突变或RAS野生型转移性结直肠癌。该试验的设计使预测性生物标志物的不断完善和伴随诊断的共同发展成为可能。在本综述中，我们着重于对胃肠道癌患者抑制HGF / c-MET途径的理解，临床靶向治疗和实施靶向HGF / c-MET的药物面临的重大挑战方面的进展，并讨论了各种努力，以及发现和验证生物标记物的相关障碍，将在这种情况下使患者分层。