MET inhibitors are a specialized type of medication used in cancer treatment. Unlike traditional chemotherapy, these targeted therapies precisely interfere with specific molecular irregularities that drive tumor growth and survival. They are designed to block a particular pathway that becomes overactive in certain cancers, reflecting a growing understanding of cancer biology and allowing for more tailored therapeutic strategies.
The MET Signaling Pathway in Cancer
The MET signaling pathway regulates cell growth, movement, and survival in healthy cells. It involves the MET proto-oncogene, which produces the MET receptor tyrosine kinase. This receptor receives signals from hepatocyte growth factor (HGF). When HGF binds, it triggers internal signals that instruct the cell to grow, divide, or move.
In some cancers, genetic alterations disrupt this regulation, causing the MET pathway to become continuously active, like an accelerator pedal stuck “on.” One alteration is MET amplification, where cancer cells have too many copies of the MET gene, leading to an overabundance of MET receptors. Another is a MET exon 14 skipping mutation, where a segment of the MET gene’s code (exon 14) is abnormally excluded. This exon normally marks the MET protein for degradation, so its removal leads to the accumulation of stable, active MET receptors, driving uncontrolled cancer cell growth.
Mechanism of Action
MET inhibitors are small molecule drugs designed to counteract the overactivity of the MET protein. They work by fitting into a specific region within the MET receptor called the ATP-binding pocket. This pocket is where adenosine triphosphate (ATP) normally binds to activate the MET protein’s signaling.
By occupying this site, MET inhibitors block ATP from attaching to the MET receptor. This prevents the MET protein from undergoing phosphorylation, which is necessary for it to send growth signals inside the cancer cell. This action effectively turns off the MET pathway, reducing uncontrolled cancer cell proliferation and survival. This targeted blockage aims to slow tumor growth and, in some cases, induce the death of malignant cells.
Cancers Targeted by MET Inhibition
MET inhibitors are primarily used for non-small cell lung cancer (NSCLC) with MET alterations. A key application is for metastatic NSCLC with MET exon 14 skipping mutations, a genetic change found in approximately 3% to 4% of NSCLC cases. For this specific indication, two oral medications, capmatinib (Tabrecta) and tepotinib (Tepmetko), are approved by the U.S. Food and Drug Administration (FDA).
MET alterations are also found in other cancers where MET inhibitors are used or being investigated. These include papillary renal cell carcinoma, a kidney cancer where MET amplification is a known driver, and certain gastric (stomach) and hepatocellular (liver) cancers. Cabozantinib, another MET inhibitor, is used in papillary renal cell carcinoma. Research continues into the utility of MET-targeted therapies for various tumor types, including glioblastoma.
The Patient Experience with MET Inhibitors
MET inhibitors are typically taken orally as pills, offering convenience for many patients. Specific dosages vary by drug; for example, capmatinib is often taken twice daily, and tepotinib once daily with food. Patients are generally advised to swallow tablets whole.
Common side effects include peripheral edema (swelling, often in the limbs), nausea, vomiting, decreased appetite, and fatigue. Liver enzyme changes can also occur, requiring regular monitoring through blood tests. Healthcare teams manage these side effects with strategies such as dose adjustments, supportive medications for nausea, and recommendations like elevating limbs or using compression stockings for edema.
Treatment effectiveness is typically monitored using imaging scans to assess tumor response. While these therapies are effective, patients may eventually develop resistance over time, which is a common challenge with targeted cancer treatments.