MET inhibitors are a class of targeted therapies that treat certain cancers by specifically interfering with the function of the MET protein. These medications represent a precision medicine approach, focusing on molecular abnormalities within cancer cells rather than broadly affecting all rapidly dividing cells like traditional chemotherapy. This targeted strategy aims to offer more effective treatment options for patients whose cancers are driven by specific MET alterations.
The Role of MET in Cancer
The MET protein, a receptor tyrosine kinase, is found on the surface of various cells. It normally plays a role in cell growth, survival, movement, and tissue repair, including wound healing and organ development. The MET protein is activated when it binds to its natural partner, hepatocyte growth factor (HGF), triggering a series of signals inside the cell. This activation leads to a cascade of downstream signaling pathways, including MAPK, PI3K/AKT, and STAT pathways, which regulate cellular functions.
Abnormal MET activity can contribute to cancer development and progression. This dysregulation often occurs through oncogenic alterations, such as MET gene amplification, overexpression, or specific mutations like exon 14 skipping. Overactive MET signaling can promote uncontrolled tumor growth, enhance cell scattering and invasion, and facilitate metastasis. Aberrant MET signaling can also contribute to resistance to other cancer therapies, including those targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways.
Targeting MET: How Inhibitors Function
MET inhibitors work by blocking the aberrant signaling pathways initiated by the MET protein, thereby disrupting processes that are necessary for tumor progression. This targeted approach aims to reduce tumor cell proliferation, survival, invasion, and angiogenesis, which is the formation of new blood vessels that feed the tumor.
There are two primary types of MET inhibitors: small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Small molecule TKIs, such as capmatinib, tepotinib, and savolitinib, are oral medications that directly enter cells and block the enzyme activity of the MET receptor by occupying its ATP-binding site, preventing it from sending growth and survival signals. Monoclonal antibodies are typically administered intravenously, working by binding to the MET receptor on the cell surface or neutralizing its ligand, HGF, to prevent their interaction and subsequent activation of the MET pathway. This disruption affects downstream signaling cascades like the PI3K/AKT and RAS/RAF/MEK/ERK pathways, which are involved in cell proliferation and survival.
Cancers Treated with MET Inhibitors
MET inhibitors treat specific types of cancers where MET alterations are present, including MET gene amplification, overexpression, and exon 14 skipping mutations. Identifying these genetic changes through biomarker testing is important to determine if a patient is likely to benefit from MET-targeted therapies. Next-generation sequencing (NGS) is a common method for detecting these alterations, often performed on tumor tissue or sometimes through a liquid biopsy using a blood sample.
Non-small cell lung cancer (NSCLC) is a primary focus for MET inhibitors, particularly in cases with MET exon 14 skipping mutations, which occur in about 3% to 4% of NSCLC patients. Capmatinib and tepotinib are approved for use in NSCLC patients with these specific mutations. MET gene amplification, though less common, is also a relevant alteration in NSCLC, and its presence can indicate a potential response to MET inhibitors. In gastric cancer, MET protein overexpression is observed in 39%–60% of cases, and MET amplification is also found in a subset of upper gastrointestinal tumors, making it a target for investigation. While some early phase trials showed promise, broader benefits in gastric cancer have been inconsistent, though savolitinib has shown activity in MET-amplified gastric cancer models. MET inhibitors are also being explored in other cancers, including papillary renal cell carcinoma and hepatocellular carcinoma.
Navigating Treatment with MET Inhibitors
Patients undergoing treatment with MET inhibitors should be aware of potential side effects and the importance of close monitoring by their healthcare team. Common side effects can include peripheral edema (swelling, particularly in the feet and legs), nausea, fatigue, and elevations in liver enzymes. Peripheral edema is a frequently reported adverse event, affecting 50% to 63% of patients, with severe cases occurring in 1% to 11%. Nausea has been reported in 26% to 46% of patients.
Managing these side effects often involves proactive communication with the healthcare team. For swelling, elevating the affected limbs and discussing the use of compression garments can be helpful, although diuretics may not always be effective. Nausea can sometimes be managed with preventative anti-nausea medication. Regular monitoring, including blood tests, is important to track liver function, kidney function, and electrolyte levels, as these can be affected by MET inhibitors. Side effects can still impact quality of life and may require dose adjustments or temporary treatment interruptions, which should always be done in consultation with a healthcare professional.