IGF1R mutations are found in many types of cancer, including breast cancer, prostate cancer, gastric cancer, lung cancer, colorectal cancer, and sarcomas.
IGF1R encodes an insulin receptor.
In healthy tissue, IGF1R helps signal to a cell that it’s time to grow or divide. When mutated, it may signal too often, leading to uncontrolled cell division, or it may produce too many receptors for insulin, causing cells to grow at a faster rate.
IGF1R is just one step in a longer chain of cellular events, called a pathway. The IGF1R pathway is one of the most studied in cancer.
IGF1R testing requires a tumor sample, ideally one taken during a recent biopsy.
Researchers are working hard to identify predictive models and combination therapies for patients with an IGF1R mutation. Drugs that inhibit IGF1R, called tyrosine kinase inhibitors, have had mixed results in clinical trials.
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We humans have an elaborate relationship with insulin, the hormone that instructs our body on how to process the food we eat. In healthy individuals, insulin tells us if we should immediately process the food we eat or if we should store it in a usable form for later. The hormone is also involved in human health: too little insulin can lead to conditions like diabetes. Overactivity of insulin—and associated players and pathways—can lead to conditions like cancer.
One of the main players that helps insulin do its job in the human body is IGF1R. IGF1R is a gene that encodes for the IGF1R (insulin-like growth factor 1 receptor) protein. As the name suggests, the protein is a receptor for its binding partner, insulin-like growth factor 1 (IGF1). IGF1 is a hormone very similar to insulin in shape and size, capable of instructing cells and tissues to grow as we progress throughout life.
The protein IGF1R belongs to a group of proteins called “receptor tyrosine kinases,” which means that the protein needs cellular energy in the form of ATP to perform its functions and instruct the cell to proliferate. Without both its binding partner (IGF1) and ATP, IGF1R sits patiently, perched on the cell membrane of nearly all tissues, awaiting signals from the hormone. When IGF1 binds to its receptor, IGF1R becomes “activated” and turns on the necessary signals for the cell to grow and divide. It’s important to say here that IGF1R can inform cells to grow via multiple pathways. The growth signals that are relayed through IGF1R are critical for growth in both developmental and adult stages of life.
Under cancerous conditions, the story is a little different. Very frequently, mutations—or changes in the DNA—make normal genes go awry. Since IGF1R is found in nearly all tissue types, mutations in IGF1R have been found in myriad cancers: breast, prostate, gastric, lung, and colorectal cancers, as well as sarcomas, among others.
There are two ways mutations in IGF1R can be involved in cancer. In the first, the mutations in the gene sequence of IGF1R encode for a slightly different form of the protein, so that the protein is constantly locked in an “on” state. If the proteins are constantly on, so are the subsequent survival and cell-division pathways. These mutations would inevitably cause the cell to constantly divide, making them more resistant to death. When the rate of cell division far exceeds the rate of cell death, tumors can form.
The second way IGF1R is involved in cancer is when mutations arise that increase the amount of protein on the surface membrane. These types of changes in IGF1R expression have been seen in lung, ovarian, pancreatic, breast, and colorectal cancer patients. In this case, the receptor itself is not locked in an “on” state, but there happens to be an excess of protein. The excess of IGF1R increases the likelihood that IGF1 will bind to it, causing the cell to grow at a faster rate.
These two ways IGF1R can cause cancer are mutually exclusive: that is, a cell doesn’t need two ways to constantly divide through the IGF1R protein. One method is enough for a normal cell to become a tumor cell. However, it’s unlikely that changes in IGF1R alone will lead to a patient getting cancer. Since cancer cells are actively dividing, the chance of other genes becoming mutated is also very high. For example, IGF1R mutations are seen alongside mutations in KRAS, another gene that encodes for a protein involved in cell division, in some lung cancer patients. IGF1R mutations also coexist with BRCA1 mutations in breast cancer. The sum of all the mutations in a particular tumor help sustain tumor growth.
In the mid-2000s, drug companies started developing many inhibitors for IGF1R, since the gene is mutated in a variety of cancers. The medical community first became excited about IGF1R inhibitors when ganitumab, a drug developed by pharmaceutical giant Amgen, cured a patient with a form of Ewing sarcoma that could not be treated by chemotherapy. The excitement continued when a drug called figitumumab, developed by Pfizer, worked in combination with chemotherapy to cure a patient with non-small-cell lung cancer. But those days of excitement are over: scientists have since learned that ganitumab actually worsened overall survival in women with postmenopausal breast cancer. Two large clinical trials for figitumumab were halted because the drug had formerly unknown major toxicities and limited effectiveness.
However, according to the scientific literature, more than 10 drugs targeting the IGF1R protein had entered clinical trials by 2013. Despite the limited effectiveness of the aforementioned inhibitors, the IGF1R pathway is one of the most extensively studied in cancer, and pharmaceutical companies are still trying to develop successful drugs against the protein. Companies have tried to develop antibodies that can bind to the exterior side of the receptor (to occlude binding of IGF1), or drugs that can fit into the energy-binding groove on the interior of the receptor (so the protein cannot be activated). But, to date, the most efficient way to shut down the IGF1R pathway is not known.
Many experts believe that the biggest issue in developing drugs against IGF1R has been the lack of efficacy and the inability to predict—using genetic markers—whether a patient will respond to the drug. So researchers and clinicians are looking into ways to use drugs against other receptor tyrosine kinases and combination therapy to help patients who have mutations in IGF1R, a finicky gene when it becomes involved in tumors. As mentioned earlier, there are multiple signaling pathways within a cell that tell it to grow and divide. Therefore, in many ways, trying to block the IGF1R protein is like playing a game of whack-a-mole: even if you take down one way the cell uses for survival, the cancer cell can find a way to bypass it; another survival pathway would “pop up,” and then doctors would have to try and knock it down yet again.
Although potent ways of targeting IGF1R directly do not yet exist, researchers are working hard to identify predictive markers and combinations of therapy for patients who have the gene mutated. Ultimately, the way you decide to be treated should be discussed at length with your clinician, who can provide specific information on what your options are.