The Story of NTRK1, NTRK2, & NTRK3
A frozen colon tumor sample yields a genetic abnormality that is eventually found in many cancers.
In the winter of 1981, two research technicians at the National Cancer Institute in Bethesda, Maryland took a scalpel to human tumor samples. The samples had been removed from patients during surgery, and some had been frozen at -70 degrees Celsius for several years. The technicians cut away the thawed tissue, snipped it into smaller pieces with scissors, and mixed it with a series of chemical solutions to extract DNA.
Simonetta Pulciani, a young researcher who had recently arrived in the United States from Rome, then introduced the tumor DNA into mouse cells. Some of the cells, she hoped, would pick up the human genes that had caused cancer in the patients. By looking for mouse cells that grew abnormally, Pulciani and her colleagues might be able to identify the critical DNA fragments responsible for the tumors.
The work was high-pressure. When Pulciani’s initial experiments with the mouse cells appeared to work, “I was so nervous that I almost killed them,” she recalls. Luckily, the cells continued to grow, and the team eventually found three DNA fragments that caused abnormal growth. One fragment, which came from the colon tumor of a 57-year-old man, was simply named “onc D.” At the time, Pulciani and her colleagues didn’t know what onc D was. “We didn’t have any idea,” she says.
Other scientists on the team examined onc D more closely and discovered that it was a gene fusion. A gene fusion is generated when DNA is rearranged: A piece of one gene is incorrectly stitched to a piece of another gene, creating a hybrid. In this case, one of the genes involved appeared to encode a receptor—a protein that receives and sends signals in the cell. “[I]t seems that a putative receptor gene has been decapitated,” the researchers wrote in the scientific journal Nature in 1986.
Researchers eventually learned that this gene, now named NTRK1, plays a critical role in helping the nervous system develop and function. The gene encodes a protein named TRKA, which is embedded in the membranes of cells. When a certain molecule binds to TRKA, the protein is activated and transmits signals to other proteins. Those signals direct nerve cells to divide and adopt more specialized functions, among other processes.
When TRKA fails to work, nervous system processes such as pain sensation can go awry. For example, researchers have linked mutations in the NTRK1 gene to a disease called congenital insensitivity to pain with anhidrosis (CIPA). Patients with this disorder do not feel pain, and they often mutilate themselves by biting their tongue, lips, and fingers. CIPA patients also suffer from mental retardation and can’t sweat. These symptoms result from a defective TRKA protein, which prevents normal development of the nervous system.
Cancer patients have the opposite problem. The TRKA fusion protein is activated—but it is activated all the time. The protein is supposed to turn on only when a certain molecule binds to it. But when it is fused to part of another protein, it constantly sends signals even when it should be silent. The turn on and don’t shut off, resulting in incessant signaling driving tumor growth. To make matters worse, the protein is produced in parts of the body where it wouldn’t normally be made.
After the fusion protein was discovered in colon cancer, scientists found similar NTRK1 fusions in papillary thyroid cancer. But the studies didn’t lead immediately to a new treatment. The mutation was generally uncommon, and the tools weren’t yet available to easily identify more people who carried it. “There was no way for us to even find these patients,” says David Hong, a clinical oncology drug researcher at the University of Texas MD Anderson Cancer Center in Houston.
That changed when new DNA sequencing techniques emerged, allowing researchers to quickly search for mutations in tumors. Scientists found that NTRK1 fusions were present—though often rare—in many types of cancer. For example, the mutation was reported in 3 percent of lung adenocarcinoma patients, 1 to 3 percent of glioblastoma patients, and 16 percent of spitzoid neoplasm patients.
In addition to NTRK1 fusions, scientists found fusions involving two related genes, NTRK2 and NTRK3. These genes also assist in nervous system development. They cause similar problems when fused to other genes, and these mutations have been found in cancers such as astrocytoma, secretory breast carcinoma, and mammary analogue secretory carcinoma of the salivary glands. Together, the proteins encoded by these three genes are called the TRK family.
Researchers are now working to develop treatments specifically for patients who carry TRK fusions. “These are like an Achilles heel that we can target in the clinic,” says Christine Lovly, a physician scientist and medical oncologist at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. The drugs in development typically prevent the fusion protein from activating by attaching to a pocket on the protein. Normally, this pocket binds to ATP, a molecule that provides energy. “It’s Nature’s gasoline,” says Hong. Without ATP, the fusion protein can’t send any signals.
So far, researchers have seen some promising results in a variety of tumor types, including lung, papillary thyroid, and colon cancer. While an effective TRK inhibitor is not yet on the market, patients can get their DNA tested for TRK mutations and join a clinical trial.
What makes TRK unique is that the fusion proteins occur in many tumor types, and—in the best-case scenario—one drug could potentially treat patients carrying the mutation regardless of where their cancer occurs. In contrast, existing cancer drugs often work mainly in one type of tumor. “What this gene is potentially enabling is a new way to look at cancer,” says Hornby.
Researchers still need to find all the tumor types where TRK fusion proteins occur and determine how common they are. And diagnostic testing for these mutations is not yet routine. For example, the fusions are found in melanoma, but melanoma patients are rarely tested for TRK. “That’s probably one of the biggest barriers,” says Robert Doebele, a medical oncologist at the University of Colorado School of Medicine in Aurora.
If a drug is brought to market, patients may be able to finally reap the benefits of a discovery made more than three decades ago. Often, patients with TRK fusions do not have other mutations commonly found in cancer patients. That means that the TRK mutation is likely driving the tumor growth—and those patients can’t try drugs that target other mutations. With a TRK inhibitor, their treatment choices could expand. “You’re talking about offering patients another option,” says Lovly.