Anaplastic Lymphoma Kinase Gene Mutation
Anaplastic lymphoma kinase (ALK) gene mutations play a key role in several types of cancer, particularly affecting younger people and nonsmokers with lung cancer.
Table of contents
- What is ALK?
- How ALK Works in the Body
- Cancers Associated with ALK Gene Changes
- Who Gets ALK-Related Cancers?
- How is ALK Gene Mutation Diagnosed?
- Treatment Options
What is ALK?
The ALK gene provides instructions for making a protein called ALK receptor tyrosine kinase. This protein is part of a family of proteins called receptor tyrosine kinases (RTKs), which transmit signals from the cell surface into the cell through a process called signal transduction[4].
ALK is a naturally occurring gene that exists in all of us. The gene is located on chromosome 2 and produces a protein of approximately 200-220 kDa in size. This protein acts as a classical receptor tyrosine kinase with an outer part that binds to signaling molecules, a middle part that crosses the cell membrane, and an inner part that has kinase activity[5].
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ALK receptor tyrosine kinase, CD246, anaplastic lymphoma kinase, ALK tyrosine kinase receptor
How ALK Works in the Body
Under normal circumstances, the ALK protein is expressed mainly in the adult human brain, where it plays a role in the development and function of the nervous system. It is also present in small intestine, testis, prostate, and colon[5].
The ALK protein becomes activated when it receives a signal from outside the cell. This causes two ALK proteins to come together in a process called dimerization. After this pairing, the protein adds phosphate groups to itself in a process called phosphorylation. This activation allows ALK to transfer phosphate groups to other proteins inside the cell, starting a chain reaction that affects important processes like cell growth and division[4].
When activated, ALK turns on multiple signaling pathways inside cells. These include pathways known as JAK-STAT, PI3K-AKT, mTOR, and MAPK. These cascades affect cell growth, transformation, and signals that prevent cell death[5].
- Brain
- Small intestine
- Testis
- Prostate
- Colon
- Lungs (when mutated)
- Lymph nodes (when mutated)
Cancers Associated with ALK Gene Changes
Changes to the ALK gene can cause several types of cancer. These changes include gene rearrangements (also called fusions), mutations, amplification (extra copies of the gene), or protein overexpression[5].
The ALK gene was first discovered in 1994 in anaplastic large cell lymphoma (ALCL). In this cancer, a piece of chromosome 2 switches places with a piece of chromosome 5, creating a fusion between the ALK gene and another gene called NPM. This creates an abnormal protein that is always active, causing cancer cells to grow[2].
In lung cancer, specifically non-small cell lung cancer (NSCLC), the ALK gene most commonly fuses with a gene called EML4. This fusion produces an abnormal ALK protein that causes cancer cells to grow and spread. About 5% of people with NSCLC have tumors with an ALK fusion. This type of lung cancer is usually adenocarcinoma, which starts in the mucus-producing glands of the lungs[7][16].
ALK gene mutations have also been identified in some people with neuroblastoma, a type of cancerous tumor composed of immature nerve cells. At least 16 mutations in the ALK gene have been found in neuroblastoma cases. The most common mutation replaces one amino acid (arginine) with another (glutamine) at position 1275. Occasionally, extra copies of the ALK gene are found in people with neuroblastoma, which results in too much ALK protein being made[4].
Other cancers where ALK gene rearrangements have been identified include inflammatory myofibroblastic tumors and rare forms of breast cancer associated with breast implants[5][6].
Who Gets ALK-Related Cancers?
People with ALK-positive lung cancer tend to be younger than the average person with lung cancer. The median age at diagnosis is 52 years, with about half of all ALK-positive lung cancer patients diagnosed when they are 50 or younger. Some people are diagnosed in their teens or 20s[7][17].
Unlike many other lung cancers, ALK-positive lung cancer is more common in nonsmokers or light smokers. It is not thought to be linked to other known causes of lung cancer such as asbestos or air pollution. The mutation is considered an “acquired mutation,” meaning the fusion occurred during a person’s lifetime due to various factors, rather than being inherited from parents[7][16].
For ALCL, ALK-positive forms mostly affect children, adolescents, and adults in their 20s and 30s. It is significantly more common in men. ALK-negative ALCL mainly affects people over 60[6].
How is ALK Gene Mutation Diagnosed?
After being diagnosed with lung cancer, patients should ask their doctor for comprehensive biomarker testing. This testing checks the lung cancer for a full list of biomarkers, including ALK, that doctors have linked to NSCLC. It is important to know if you have any biomarkers to help decide treatment options, as different treatments work better on cancers with certain biomarkers[16].
There are two main types of biomarker testing. During a tissue biopsy, doctors use a sharp tool to get a sample of tissue from the lung cancer tumor. During a liquid biopsy, doctors take a sample of blood to look for cancer cells from the tumor circulating in the blood. Currently, tissue biopsies are the standard of care if enough tissue is available, but liquid biopsies are showing promise for the future[16].
If the biomarker test shows ALK-positive cancer, doctors may refer to it using different terms including ALK mutation, ALK biomarker, ALK fusion, ALK rearrangement, or ALK-positive lung cancer or lymphoma[16].
For ALCL, the different types are classified based on whether there is a mutation in the ALK gene. Forms with the mutation are called “ALK-positive” ALCL, while those without the mutation are called “ALK-negative”[6].
Treatment Options
ALK-positive cancers can be treated with targeted therapy, which is a type of treatment that finds and attacks certain parts of cancer cells. These therapies prevent the growth of cancer cells only and do not harm healthy cells[16].
The specific type of targeted therapy used for ALK-positive cancers are drugs called tyrosine kinase inhibitors (TKIs). These drugs block the abnormal signals that tell cancer cells to grow and spread. When you receive a TKI, the drug blocks the signal from reaching the receptor, which means the cancer cells do not receive messages to grow out of control[16].
The first ALK inhibitor developed was crizotinib. Since then, newer drugs have been created including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib. Studies have shown that people treated with ALK-targeted drugs lived longer without their cancer growing compared to those receiving chemotherapy. These improvements were seen even in people whose cancer had spread to the brain[12].
Research shows that newer ALK-targeted drugs work better than crizotinib as first treatment. People treated with newer ALK-targeted drugs such as alectinib, brigatinib, ceritinib, or lorlatinib lived longer without their cancer growing and were more likely to live longer overall[12].
For ALK-positive lung cancer patients, targeted therapy often causes tumors to reduce in size dramatically and results in a longer time until symptoms worsen compared to chemotherapy. With treatment, about half of people with stage IV ALK-positive lung cancer live nearly 7 years or longer[12][17].
ALK-targeted drugs cause a similar number of overall side effects as chemotherapy, though the types of side effects may differ. Some patients may need chemotherapy or other treatments in addition to or instead of targeted therapy, depending on their specific situation[12].
One challenge with ALK inhibitors is that cancer can develop resistance to these drugs over time. When this happens, doctors may switch to a different ALK inhibitor or recommend combination therapies. Research is ongoing to develop new strategies to overcome resistance to current ALK inhibitors[5].
