Targeted cancer therapy focuses treatment on unique molecular vulnerabilities within a tumor. Many cancers depend on specific protein signals for aggressive growth and survival, often involving protein kinases that function as cellular switches controlling proliferation. A protein kinase inhibitor is a small molecule drug designed to block these malfunctioning enzymes. MET inhibitors are a specific class of targeted drugs engineered to disrupt signaling driven by the Mesenchymal-Epithelial Transition (MET) protein, halting tumor progression.
The MET Pathway and Oncogenic Drivers
The MET protein is a receptor tyrosine kinase on the cell surface, acting as a receiver for external signals, primarily from its binding partner, Hepatocyte Growth Factor (HGF). Under normal conditions, MET signaling is transiently activated to orchestrate essential processes like embryonic development, tissue repair, and wound healing. This pathway is typically regulated by a negative feedback loop that ensures the protein is degraded after its work is done.
When the MET pathway is deregulated, it acts as an oncogenic driver, promoting tumor formation and spread. This abnormal activation usually occurs through two primary genetic alterations. The first is \(MET\) gene amplification, which results in too many copies of the gene, leading to an overabundance of the MET receptor protein on the cell surface. The second alteration is the \(MET\) exon 14 skipping mutation.
This skipping mutation causes the deletion of a segment of the gene that encodes the juxtamembrane domain of the MET protein. This deleted domain normally contains a site that recruits the enzyme Cbl, which tags the receptor for degradation. Losing this regulatory domain makes the MET receptor resistant to breakdown, leading to its constant presence and persistent signaling. This persistent signaling drives uncontrolled cell proliferation and metastasis.
Mechanism of Action: How MET Inhibitors Work
MET inhibitors are specialized small molecules designed to interfere with the function of the MET protein. Most of these drugs target the internal kinase domain of the MET receptor, the site where the protein gains its activating energy. This domain contains a specific pocket meant to bind the energy molecule adenosine triphosphate (ATP).
The inhibitors are structurally designed to mimic ATP and fit into this ATP-binding pocket. By occupying this site, the inhibitor prevents the ATP molecule from binding, blocking the phosphorylation step required to activate the MET receptor. This action shuts down the entire downstream signaling cascade, including pathways like RAS/MAPK and PI3K/AKT, which are responsible for cell growth and division.
Small molecule inhibitors are classified based on how they interact with the kinase domain’s conformation. Type I inhibitors bind to the active conformation of the protein, known as the “DFG-in” state. Type II inhibitors, in contrast, bind to the inactive “DFG-out” conformation of the kinase. This distinct binding mode allows Type II inhibitors to exploit an adjacent hydrophobic pocket, which can be effective against specific resistance mutations that render Type I inhibitors ineffective.
Current Classes and Clinical Applications
MET inhibitors fall into two major therapeutic classes: small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Small molecule TKIs are the most common and are orally available. These drugs target the internal activation domain of the MET protein. Examples of selective TKIs include capmatinib, tepotinib, and savolitinib.
The primary clinical application for these selective TKIs is in Non-Small Cell Lung Cancer (NSCLC) for patients whose tumors harbor the \(MET\) exon 14 skipping mutation. This alteration predicts response to MET inhibition, leading to the approval of these agents. High-level \(MET\) gene amplification is another indication, particularly when the amplification is pronounced.
MET amplification is also a mechanism of acquired resistance in patients initially treated with drugs targeting other pathways, such as EGFR inhibitors. Combining an EGFR inhibitor with a MET inhibitor is used to overcome this resistance. While NSCLC is the most prominent target, MET alterations also play a role in other malignancies, including gastric cancers and renal cell carcinoma.
Patient Selection and Treatment Monitoring
Identifying the correct patients requires biomarker testing before treatment begins. The presence of a targetable \(MET\) alteration must be confirmed, usually through molecular diagnostics. Next-Generation Sequencing (NGS) is the standard method used to detect the \(MET\) exon 14 skipping mutation, often analyzing both the DNA and RNA from a tumor sample.
For detecting \(MET\) gene amplification, Fluorescence In Situ Hybridization (FISH) is used, measuring the ratio of \(MET\) gene copies to a control gene copy. Only patients with confirmed, actionable \(MET\) alterations are eligible for these targeted treatments. These TKIs are typically administered orally as pills.
Treatment monitoring is necessary due to potential side effects and the development of acquired drug resistance. Common side effects include peripheral edema (swelling, particularly in the limbs) and gastrointestinal issues like nausea or diarrhea. Resistance limits drug effectiveness when cancer cells evolve new ways to bypass the drug. This resistance can involve secondary mutations within the MET kinase domain that prevent drug binding or “off-target” mechanisms, such as activating a different signaling pathway like KRAS.