More than METs the Eye
The role of different types of MET proto-oncogene mutation in lung cancer could demand a rethink of treatments.
Jonathan James | | Quick Read
The prognosis for non-small-cell lung cancer (NSCLC) patients has certainly improved in recent years – in part due to the introduction of tyrosine-kinase inhibitors. Despite an improved outlook, major concerns remain; chiefly, the role of tumor heterogeneity in drug resistant cancers – and the consequent barrier posed to treatment development.
Though mutations in MET proto-oncogene receptor tyrosine kinase (MET) are only found in 5 percent of NSCLCs, they appear to be key drivers of carcinogenesis. However, their interactions with other tumor promoting genes are less well understood. Now, researchers in Germany have revealed an important detail: differences in these mutations, characterized as either exon skipping or amplifications, correspond to differences in their role in tumor progression (1). In short, MET alterations differ not only genetically but also have a clinical impact.
Specifically, the study of 50 patients showed that, whereas exon skipping mutations in MET appear to be independent early drivers of tumor formation, MET amplifications more typically occur within a background of higher genetic instability, and may therefore play a more nuanced role in tumor progression. Indeed, survival analysis demonstrated that MET amplifications typically reduce patient survival by an additional 25 percent compared with MET exon-skipping mutations.
The authors note the limitations of the study (analysis of only a restricted number of genes and a relatively small number of patients) but indicate that a core assumption of current clinical trials – in which MET inhibitors are applied globally to all mutational types – may have to be rethought; instead, Castiglione and his team believe that MET-specific treatment options may need more careful tailoring to the genetic background of each patient’s tumor.
- R Castiglione et al., “Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies”, Modern Pathology, [Epub ahead of print] , PMID: 30459450.