The ALK gene, or Anaplastic Lymphoma Kinase, provides instructions for creating a protein called ALK receptor tyrosine kinase, which is part of a family of proteins that transmit signals within cells. When this gene undergoes a change, known as an ALK gene mutation, it can lead to the production of an abnormal protein. These altered proteins can then contribute to the development of certain diseases.
The ALK Gene and Its Mutations
This protein, ALK receptor tyrosine kinase, plays a role in signal transduction, a process where signals are transmitted from the cell surface into the cell. This signaling is thought to help regulate the proliferation of nerve cells, particularly early in development.
A mutation or rearrangement in the ALK gene can lead to an abnormal ALK protein that is constantly active, even without external stimulation. This continuous activation can happen through various mechanisms, such as a gene fusion, where a portion of the ALK gene combines with another gene. For example, an inversion on chromosome 2 can fuse the ALK gene with the EML4 gene, creating an EML4-ALK fusion protein.
These gene fusions allow the ALK receptor tyrosine kinase to become activated without its usual dimerization process, leading to uncontrolled signaling. The resulting overactive ALK protein can then promote abnormal cell growth and survival. Such mutations are typically acquired during a person’s lifetime (somatic mutations) rather than being inherited (germline mutations), meaning they are present only in the cancerous cells.
Cancers Associated with ALK Mutations
ALK gene mutations are associated with several types of cancer, with Non-Small Cell Lung Cancer (NSCLC) being the most common. ALK rearrangements are found in approximately 3-7% of NSCLC cases, primarily in adenocarcinomas. This prevalence translates to potentially 40,000 new cases worldwide each year. Patients with ALK-positive NSCLC are often younger and may have a never or light smoking history.
Beyond NSCLC, ALK mutations also play a role in Anaplastic Large Cell Lymphoma (ALCL), a type of T-cell lymphoma. About 6-7% of mature T-cell lymphomas are ALK-positive ALCL. In children and teenagers, approximately 90% of ALCLs are ALK-fusion-positive, while in adults, this figure is around 50%. The most frequent fusion partner in ALCL is NPM1, forming the NPM-ALK fusion protein in about 70-80% of cases.
Neuroblastoma, a cancer of early childhood, also frequently involves ALK mutations. Somatic ALK mutations are found in 6-10% of neuroblastoma patients at diagnosis, with an even higher incidence reported at relapse. These mutations often occur at specific hotspots within the ALK tyrosine kinase domain.
Additionally, Inflammatory Myofibroblastic Tumors (IMT), rare soft tissue neoplasms, frequently exhibit ALK gene rearrangements or fusions, observed in approximately 50-70% of cases. While ALK point mutations are less common in IMT, they can occur. The presence of ALK fusions in IMT has been validated as a therapeutic target.
Identifying ALK Mutations
Fluorescence In Situ Hybridization (FISH) is a technique that visualizes specific chromosomal rearrangements. For ALK, FISH uses fluorescent probes that bind to parts of the ALK gene on chromosome 2. A “break-apart” FISH assay can detect rearrangements by showing a separation of signals, indicating a gene fusion. This method is considered a reference standard for detecting ALK rearrangements.
Immunohistochemistry (IHC) is another method that detects the presence and overexpression of the ALK protein in tissue samples. IHC is often used as a screening tool due to its cost-effectiveness and relatively quick turnaround time, with positive results often confirmed by other methods.
Next-Generation Sequencing (NGS) offers a comprehensive approach by simultaneously screening for multiple genetic alterations, including ALK fusions and point mutations. This method can identify the specific fusion partners and genomic breakpoints, providing detailed information about the mutation. NGS can be performed on tumor tissue or liquid biopsies, allowing for dynamic monitoring of mutations during treatment. The ability of NGS to detect novel mutations and track changes in mutation frequencies makes it a valuable tool for guiding treatment decisions.
Targeted Therapies for ALK-Positive Cancers
Targeted therapies for ALK-positive cancers focus on inhibiting the abnormal ALK protein. These drugs, known as ALK inhibitors or tyrosine kinase inhibitors (TKIs), work by binding to the ATP pocket of the altered ALK protein, thereby blocking its energy access and deactivating it. This action prevents the continuous signaling that drives cancer cell growth and survival.
Several ALK inhibitor drugs have transformed the treatment landscape for ALK-positive cancers. Crizotinib was the first-generation ALK inhibitor approved, also targeting ROS1 and MET. Subsequent generations, including alectinib, ceritinib, and brigatinib, are considered second-generation inhibitors. These newer agents generally demonstrate higher potency against ALK and can overcome some resistance mutations that may develop with crizotinib, and many are effective against brain metastases.
Lorlatinib represents a third-generation ALK inhibitor, designed to overcome a broader range of ALK resistance mutations and effectively penetrate the blood-brain barrier. It has shown strong activity against common resistance mutations like G1202R, which can mediate resistance to earlier-generation ALK TKIs. Despite the effectiveness of these therapies, drug resistance can still develop, often through secondary ALK mutations or activation of alternative signaling pathways. Ongoing research continues to explore new inhibitors and combination therapies to address these resistance mechanisms.