Anaplastic lymphoma kinase (ALK) is a protein that helps regulate cell growth. It is a type of enzyme called a receptor tyrosine kinase, which acts as a switch in the body’s cell signaling network. The gene providing instructions for this protein is also called ALK. While this protein has specific functions in normal development, it is often studied for its connection to cancer. When the ALK gene undergoes certain changes, it can produce an abnormal protein that drives tumor development, making it a factor in several specific types of cancer.
The Role of ALK in Normal Cell Development
The ALK protein is active during the earliest stages of human development, contributing to the formation of the nervous system, gut, and brain in an embryo. Located on the surface of cells, the ALK protein acts like a switch. When a specific molecule binds to the outside of the protein, it activates a function on the inside of the cell, triggering signals that instruct the cell to grow and divide. This process is tightly controlled to ensure tissues and organs form correctly. After embryonic development is complete, the ALK gene is expressed at very low levels in most adult tissues, as its job is largely finished.
How ALK Gene Changes Lead to Cancer
Cancer linked to ALK is caused by an altered version of the protein that results from a genetic mistake called a gene rearrangement. During this event, a piece of the chromosome with the ALK gene breaks off and fuses with a piece of another chromosome. A common fusion partner is the EML4 gene, creating a new, hybrid gene known as EML4-ALK. This fusion gene produces an abnormal ALK protein that is permanently activated. Unlike the normal protein, which requires a signal to turn on, this fusion protein is stuck in the “on” position, constantly telling the cell to grow and divide without stopping. This unregulated signaling leads to the formation of tumors, as the abnormal protein activates multiple pathways inside the cell associated with proliferation and survival.
Cancers Driven by ALK Gene Changes
ALK gene alterations have led to the identification of distinct subtypes of several cancers. The most prominent is non-small cell lung cancer (NSCLC), where ALK rearrangements are found in about 4% of patients. This form of lung cancer, ALK-positive NSCLC, is often diagnosed in people who are younger than the average lung cancer patient and who have little or no history of smoking. The genetic alteration was first identified in a type of non-Hodgkin lymphoma called anaplastic large cell lymphoma (ALCL), which is where the “AL” in ALK comes from. ALK gene changes have also been found in neuroblastoma, a nerve tissue cancer affecting young children, and inflammatory myofibroblastic tumors, which are rare soft tissue tumors.
Testing for ALK-Positive Cancers
Identifying an ALK gene rearrangement is a standard diagnostic step for certain cancers, like advanced non-squamous NSCLC. Testing is performed on a tumor biopsy, where a small sample of cancerous tissue is removed for laboratory analysis. Several methods can detect the altered ALK gene or protein.
One common test is immunohistochemistry (IHC), which uses antibodies to stain the tissue sample. If the ALK protein is present in high amounts, the cells change color. Another method is fluorescence in situ hybridization (FISH), which uses fluorescent probes that attach to specific parts of the ALK gene. If the gene is rearranged, the probes will appear in an abnormal pattern under a microscope. A more comprehensive approach is next-generation sequencing (NGS), which analyzes a tumor’s genetic makeup to identify the specific ALK fusion partner.
Targeted Therapy for ALK-Positive Cancers
The identification of ALK as a cancer driver led to the development of targeted therapies known as ALK inhibitors. These medications are designed to block the activity of the abnormal ALK fusion protein. Unlike traditional chemotherapy, ALK inhibitors precisely target the molecular driver of the cancer, stopping the signals that tell cancer cells to grow. This approach often results in fewer side effects.
Several generations of ALK inhibitors have been developed to be more effective and to overcome treatment resistance. These include:
- Crizotinib
- Alectinib
- Brigatinib
- Lorlatinib
Resistance can occur when cancer cells develop new mutations that make the initial drug less effective. For some patients with early-stage disease, an ALK inhibitor may be used after surgery to reduce the risk of recurrence.