We are progressively moving from treating lung cancer as one disease, to an era of lung cancer being a collection of separate subtypes, each driven by an oncogenic mutation that contributes to cancer initiation, progression and metastasis. We are now filling out the lung cancer pie-chart for these individual subtypes, and beginning to understand each one of them better- oncogenic drivers for these subtypes are being identified and therapies targeted against each of these are increasingly being developed and tested. One sliver of this pie-chart is the recently identified MET exon-14 skipping mutation, which is seen in 4% of all lung adenocarcinomas, and a subset of small cell lung cancers.
WHY IS THE MET GENE IMPORTANT? The MET gene produces the MET protein, also known as Hepatocyte Growth Factor Receptor (HGFR), which is a receptor tyrosine kinase. MET plays important physiological roles in development and tissue repair, driving central processes such as cell proliferation, apoptosis, and motility/invasion essential for the normal functioning of the body.
WHAT ALTERATIONS IN MET AR’;lkE SEEN IN LUNG CANCER? Several aberrations in MET signaling have been identified in various cancers. In lung cancer, alterations in MET have been observed in 3% of squamous cell lung cancer patients, and 8% lung adenocarcinomas. The three most common alterations in MET seen in lung cancer are: 1) MET protein overexpression, 2) MET gene amplification, and 3) the recently identified MET exon 14 skipping. These alterations in MET signaling might occur de novo in lung tumors (being in tumors from the get-go) or, might emerge as a mechanism of resistance to targeted therapy against other lung cancer oncogenic drivers, such as EGFR, e.g. MET amplification has been shown to be a major mechanism by which cancers develop resistance to EGFR inhibitors.
WHY IS THE MET EXON-14 SKIPPING MUTATION ONCOGENIC? In a normal cell, all proteins have a ‘shelf-life’, after which they are degraded by the cell’s machinery making way for new proteins. The MET exon 14 skipping mutation causes the loss of a segment of the MET protein, making it more ‘stable’ i.e. resistant to degradation, prolonging its signaling activity, thereby potentiating its pro-cancer capacity. Like mentioned previously, MET exon 14 skipping is seen in 4% lung adenocarcinoma patients, which is approximately the same percentage of patients that harbor aberrations in the ALK gene, translating into approximately 7,000 patients each year in the United States alone.
HOW CAN THESE MUTATIONS BE TARGETED? The MET protein belongs to a category of proteins called the receptor tyrosine kinases that also includes the EGFR and ALK proteins. There are several receptor tyrosine kinase inhibitors that have demonstrated preclinical activity (in cancer cell lines) against MET, the most prominent being crizotinib (Xalkori) and cabozantinib (Cometriq). The first evidence of activity of these inhibitors in lung cancer patients was presented at the 2015 ASCO Annual Meeting earlier this year- these data demonstrated that treating lung adenocarcinoma patients with the MET exon-14 skipping mutations with MET-inhibitors, crizotinib or cabozantinib resulted in responses for the majority of patients. At the recently concluded, 16th World Conference on Lung Cancer, additional data was presented showing a response to crizotinib in 4 of 5 patients with MET exon-14 skipping mutations. These early data show that this subset of lung cancer is potentially targetable with inhibitors that have already been approved in other settings for cancer patients.
WHAT CAN PATIENTS WITH MET EXON 14 SKIPPING MUTATIONS DO NOW? Since data on targeting these mutations is only now emerging, and none of these therapies has been approved for these specific subsets of lung cancer, patients with MET exon 14 skipping mutations should ideally be treated in the context of a clinical trial of a MET inhibitor. For patients who do not have access to a clinical trial and for whom standard therapy does not exist, use of off-label crizotinib should be considered.