Genes are the fundamental units of heredity, composed of DNA, which provide instructions for building and maintaining an organism. These instructions often guide the production of proteins, molecules that carry out a vast array of functions within the body. While most genes are identical across individuals, minor variations contribute to unique physical traits and can also influence health outcomes.
What the ALK Gene Is
The ALK gene, short for Anaplastic Lymphoma Kinase, provides instructions for creating a protein known as ALK receptor tyrosine kinase. This protein belongs to a family of proteins called receptor tyrosine kinases (RTKs), which are involved in transmitting signals from the outer surface of a cell to its interior. These signals are crucial for various cellular processes, including cell growth, division (proliferation), and maturation (differentiation).
The ALK receptor tyrosine kinase is believed to play a role in the early development of the nervous system by helping to regulate the proliferation of nerve cells. In healthy adult tissues, ALK protein activity is low. This protein is conserved across many species, with similar versions found in fruit flies, nematodes, zebrafish, and mice, suggesting its fundamental importance in biological processes. The ALK protein usually resides on the cell membrane, acting like an antenna to receive external signals and relay information inside the cell for action.
ALK Gene Alterations and Their Impact
When the ALK gene undergoes changes, it can lead to abnormal ALK protein activity, which contributes to the development of various cancers. These alterations can take several forms, including gene fusions, point mutations, and amplifications. Gene fusions, where the ALK gene breaks and joins with another gene like EML4, creating a “fusion gene” such as EML4-ALK, are a common alteration. This EML4-ALK fusion is particularly prevalent in non-small cell lung cancer (NSCLC), accounting for about 85% of ALK fusions in this cancer type.
The EML4-ALK fusion protein, for instance, can become constantly active without needing external signals, leading to uncontrolled cell growth and survival. This continuous activation drives cancer cell growth. Point mutations, a change in a single DNA building block, can also turn on the gene when it should be inactive, leading to excessive cell growth. Gene amplifications, too many copies of the ALK gene, can also result in increased ALK protein activity.
ALK alterations are associated with several types of cancer. Non-small cell lung cancer (NSCLC) is a common example, with ALK rearrangements found in 3-5% of patients, often younger individuals who are non-smokers and have adenocarcinoma. Another disease linked to ALK alterations is anaplastic large cell lymphoma (ALCL), a type of non-Hodgkin’s lymphoma. Neuroblastoma, a cancerous tumor composed of immature nerve cells, also frequently involves ALK gene alterations, particularly gain-of-function point mutations in about 14% of high-risk cases.
Detecting ALK Alterations
Identifying ALK gene alterations is important for guiding treatment decisions. Clinicians use various diagnostic methods to detect these changes in tumor samples. One widely used method is Fluorescence In Situ Hybridization (FISH), which can detect gene fusions at the DNA level by using fluorescent probes that bind to specific DNA sequences, revealing rearrangements.
Immunohistochemistry (IHC) is another common technique that detects the presence of the abnormal ALK protein in tissue samples. IHC is often used as a preliminary screening tool due to its efficiency and cost-effectiveness. Next-Generation Sequencing (NGS) offers a more comprehensive approach, detecting various ALK alterations (fusions, point mutations, and amplifications) by sequencing large portions of DNA or RNA. NGS can also identify the specific fusion partners and breakpoints, providing more detailed information.
Polymerase Chain Reaction (PCR)-based tests, such as reverse transcriptase-PCR (RT-PCR), can also detect ALK gene fusions by amplifying and identifying the specific RNA transcripts produced from these fusions. Each method has distinct advantages, and these tests are important for identifying patients who may benefit from ALK-targeted therapies.
Targeted Therapies for ALK Alterations
Targeted therapy represents a precise approach to treating cancers driven by ALK alterations, differing from traditional chemotherapy by specifically focusing on tumor cells. These therapies aim to inhibit the abnormal ALK protein, thereby disrupting the signals that promote cancer cell growth and survival. The drugs used for this purpose are known as ALK inhibitors, which are a type of tyrosine kinase inhibitor (TKI).
ALK inhibitors work by blocking the activity of the overactive ALK protein, which can slow or even halt the progression of ALK-positive cancers. Several generations of ALK inhibitors have been developed. Crizotinib was the first-generation ALK inhibitor, effective in reducing tumor size. Second-generation inhibitors like Alectinib, Brigatinib, and Ceritinib often show increased potency and can overcome some resistance mechanisms. Lorlatinib, a third-generation ALK inhibitor, is effective against a broader range of ALK resistance mutations and penetrates the blood-brain barrier more effectively, benefiting patients with brain metastases.
These targeted therapies offer significant benefits, including higher response rates and potentially fewer side effects than conventional chemotherapy. However, a challenge is the eventual development of drug resistance, where cancer cells bypass the drug’s effects. Resistance can arise from new mutations in the ALK gene or activation of alternative signaling pathways. Ongoing research focuses on developing new ALK inhibitors and combination therapies to overcome this resistance, aiming for more durable patient responses.