The MET proto-oncogene provides instructions for making the c-MET protein. This protein is a receptor on the surface of cells that receives specific signals telling the cell to grow and divide. This process is a normal, controlled part of how cells communicate. The c-MET protein is a receptor tyrosine kinase, a family of proteins that transmit signals from the cell’s exterior to its interior, which is an important capability for many cellular activities.
The Normal Function of the c-MET Pathway
The c-MET receptor responds to a specific partner molecule called hepatocyte growth factor (HGF). When HGF binds to c-MET on the cell surface, it causes two c-MET receptors to pair up in an event known as dimerization. This pairing activates the receptor, triggering a cascade of signals inside the cell that directs biological processes.
In a healthy body, the c-MET signaling pathway is carefully regulated. It plays a part in embryonic development, ensuring tissues and organs form correctly. The pathway is also involved in adult processes like tissue regeneration and wound healing. For example, if the liver is damaged, HGF is released to activate c-MET on liver cells, stimulating their growth to repair the injury.
This controlled system ensures that cell growth happens only when needed. Once a task like healing a wound is complete, the signaling is switched off to maintain normal tissue balance and cellular order.
How c-MET Drives Cancer
The controlled c-MET pathway can become dysregulated, leading to cancer. This occurs when the MET gene undergoes alterations that disrupt its normal function. These changes can cause the c-MET receptor to get stuck in the “on” position, continuously telling the cell to grow and divide without an external signal. This unchecked growth is a defining characteristic of cancer.
One common alteration is MET gene amplification, where a cell makes too many copies of the MET gene. This leads to an excessive number of c-MET receptors on the cell surface, a state called overexpression. With so many receptors, the cell becomes overly sensitive to HGF, resulting in hyperactive growth signaling.
Another alteration is a mutation within the MET gene. Certain mutations can change the c-MET protein’s structure, causing it to become permanently activated, even without HGF. A well-known example is the MET exon 14 skipping mutation, where a piece of the gene’s instructions is omitted. This produces a receptor that is not properly degraded and remains constantly active.
This constant signaling promotes uncontrolled cell proliferation and helps cancer cells survive. Activated c-MET signaling can also trigger invasion and metastasis. This is a process where cancer cells break away from the original tumor, travel through the body, and form new tumors in other locations.
Identifying c-MET Alterations in Tumors
To determine if a patient’s cancer is driven by faulty c-MET signaling, specialists analyze a tumor tissue sample from a biopsy. Laboratory techniques are used to detect specific alterations in the MET gene or c-MET protein. This information helps guide treatment decisions.
One method is immunohistochemistry (IHC), which uses antibodies that bind to the c-MET protein. A stain is applied to the tumor sample, and if an abnormally high amount of c-MET protein is present (overexpression), it becomes visible under a microscope. The stain’s intensity helps pathologists quantify the protein level.
Another approach is fluorescence in situ hybridization (FISH), which counts the number of MET gene copies to check for amplification. FISH uses fluorescent probes that attach to the MET gene. When viewed with a special microscope, these glowing probes allow pathologists to see if there are extra copies of the gene.
A comprehensive technique is next-generation sequencing (NGS), a technology that analyzes a tumor’s DNA for a wide range of genetic alterations. NGS can identify MET gene amplification and specific mutations, such as MET exon 14 skipping. An NGS panel can test for changes in many cancer-related genes, providing a detailed molecular profile of the tumor.
c-MET Inhibitors as Targeted Therapy
The discovery of c-MET’s role in cancer led to the development of c-MET inhibitors. These drugs are a form of targeted therapy designed to block the faulty c-MET receptor. Unlike traditional chemotherapy, which affects all rapidly dividing cells, these inhibitors target the specific molecular driver of the cancer.
These drugs work by binding to the c-MET receptor and preventing it from sending growth signals. By shutting down this pathway, c-MET inhibitors can halt or slow tumor growth and, in some cases, cause tumors to shrink. This approach turns off the signal that cancer cells depend on to survive.
C-MET inhibitors have shown success in treating cancers with specific MET alterations. For example, they are an established treatment for patients with non-small cell lung cancer (NSCLC) whose tumors have a MET exon 14 skipping mutation. The FDA has approved drugs like capmatinib and tepotinib for this patient group.
Research continues to explore using c-MET inhibitors in other cancers with MET alterations, including kidney, head and neck, and gastric cancers. Clinical trials are investigating combinations of c-MET inhibitors with other targeted therapies to overcome drug resistance. This strategy is an example of personalized medicine, where treatments are tailored to the genetic makeup of a patient’s tumor.