An anaplastic lymphoma kinase (ALK) fusion is a genetic alteration that can drive the growth of certain cancers. The ALK gene contains instructions for producing the ALK receptor tyrosine kinase protein. This protein’s normal function is to receive signals from outside a cell and transmit them inward, helping to regulate cell growth and division.
A gene fusion occurs when a piece of the ALK gene breaks off and attaches to a different gene, creating a new hybrid gene. This new gene produces an abnormal fusion protein that is constantly active, or “on,” without needing external signals. This sends a continuous command for the cell to grow and divide, leading to the formation of cancerous tumors.
Cancers Associated with ALK Fusion
The most prominent cancer associated with this genetic change is non-small cell lung cancer (NSCLC). ALK fusions are identified in approximately 3-5% of NSCLC patients, representing tens of thousands of new cases worldwide each year. Patients with ALK-positive NSCLC are often younger than the average lung cancer patient and typically have a history of light or no smoking.
While most common in lung cancer, ALK fusions are not exclusive to it and were first discovered in anaplastic large cell lymphoma (ALCL). This alteration is also found less frequently in other malignancies, including neuroblastoma and inflammatory myofibroblastic tumors (IMT). The presence of an ALK fusion is a defining characteristic for these cancers.
Detecting ALK Fusions
Identifying an ALK fusion is a standard part of the diagnostic process for cancers like advanced NSCLC, requiring a tumor tissue sample from a biopsy. Several specialized laboratory techniques are then used to analyze the cancer cells for the fusion.
Immunohistochemistry (IHC) is a common screening method that uses antibodies designed to stick to the ALK fusion protein. Under a microscope, a chemical reaction causes cells containing the protein to change color, visually confirming its presence.
Fluorescence in situ hybridization (FISH) looks directly at the cancer cell’s chromosomes using fluorescent probes that attach to the ALK gene. In normal cells, the probes create a single signal. In cells with an ALK fusion, the gene rearrangement causes the probes to appear separated, indicating a break.
Next-generation sequencing (NGS) is a comprehensive approach that reads large portions of a tumor’s DNA. This method provides a detailed genetic map, identifying the exact genes in the fusion and screening for other relevant mutations in the cancer.
Targeted Therapies for ALK-Positive Cancers
The discovery of ALK fusions led to targeted therapies called ALK inhibitors. Unlike chemotherapy, these medications are designed to attack cancer cells with the ALK fusion protein. This precision allows for effective treatment while causing fewer side effects related to damage to healthy cells.
ALK inhibitors work by fitting into a pocket on the fusion protein, blocking its growth signals. By shutting down this “on” switch, the drugs prevent cancer cells from multiplying and can cause them to die. This action can lead to tumor shrinkage and control the cancer’s progression.
The first ALK inhibitor was crizotinib. Research has since produced more advanced, second-generation drugs like alectinib and brigatinib, which are more potent. They were also designed to better penetrate the blood-brain barrier, as ALK-positive lung cancer can spread to the brain.
Third-generation inhibitors like lorlatinib are engineered to be effective against mutations that arise after treatment with earlier drugs has stopped working. The availability of multiple generations of ALK inhibitors provides a sequence of treatment options to manage the disease long-term.
Managing Treatment and Resistance
While treatment with ALK inhibitors can be highly effective, it is not always a permanent solution. Cancer cells can evolve and develop new mutations that allow them to bypass the drug’s effects. This is known as acquired resistance, a common challenge where the cancer may begin to grow again.
When resistance is suspected, a new biopsy of the tumor is performed. The tissue is then analyzed, typically using next-generation sequencing (NGS), to identify the genetic changes allowing the cancer to evade the ALK inhibitor.
If a specific resistance mutation is found, the patient may be switched to a different, newer-generation ALK inhibitor designed to work against that mutation. This approach of testing, treating, and re-evaluating allows for a personalized and adaptive treatment strategy. This turns the management of ALK-positive cancer into an ongoing process.