AKT mutations are found in almost all cancers.
When the AKT genes work properly, they encode proteins that pass along messages from other parts of the cell. In social-network terms, they don’t tweet, they retweet.
When the AKT genes are altered, they can cause a cell to grow and divide too often, or remain alive when it should die.
There are no AKT inhibitors currently approved by the FDA for use in cancer patients, however several potential medications are in clinical trials for cancers, including prostate cancer, breast cancer, and pancreatic cancer.
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Our cells have their own version of Facebook and Twitter. This miniature social network contains the thousands of proteins that are continually interacting to enable a cell to survive and divide—and explains why cancer can result when some of these proteins don’t work properly.
Like Facebook users with hordes of friends, the AKT proteins stand out within this network because they boast so many connections. They directly or indirectly influence hundreds of different proteins, and their networking skills put them right in the middle of many of the cell’s crucial activities.
There are three closely related AKT genes—AKT1, AKT2, and AKT3—each of which carries the instructions for making a different AKT protein. Researchers used to think that these proteins were equivalent. But recent findings suggest that each of the three siblings has unique responsibilities, and researchers are still trying to sort out their specific roles. What is clear is that AKT proteins often malfunction in cancer.
The discovery of the AKT family dates back to the late 1980s. Stephen Staal, a physician and researcher at Johns Hopkins School of Medicine in Baltimore, Maryland, stumbled on an AKT gene in a surprising place—inside a virus that infects mice. He and two fellow researchers found the virus in 1977, and learned that it spurred tumors to grow in the animals. Few viruses trigger development of cancer. The cold and flu viruses that make us miserable every winter don’t cause cancer, for instance, although the hepatitis B virus can.
To understand how the mouse virus unleashed tumors, Staal parsed its genes. He discovered that the virus had swiped one of its genes from its rodent hosts. The pilfered gene helps the virus achieve its goal—forcing cells to make more viruses. In the process, the gene induces some of those cells to become cancerous.
Using different techniques, other groups of researchers also identified AKT at about the same time. But Staal hit upon a connection to human cancers. When he analyzed human DNA, he came across two slightly different versions of the gene he’d discovered in the virus, which he named AKT1 and AKT2. That finding showed that AKT genes normally occur in our cells. Then Staal scrutinized cells from a person who had stomach cancer. The patient’s tumor cells carried 20 times as many copies of AKT1 as did healthy cells, providing the first link between AKT genes and cancer in people.
Staal soon moved on to new topics, but other scientists stepped in and figured out how the AKT proteins fit into the cell’s social network. The interacting proteins in this network work together to coordinate the cell’s metabolism, growth, and reproduction. AKT proteins serve as a well-connected hub for the network, passing on crucial messages they receive from other proteins. In social-network terms, AKT proteins don’t tweet, they retweet.
One reason that AKT proteins are so influential is that they relay messages they receive from proteins that respond to commands from other cells. Certain cells in our bodies release growth factors that tell other cells it’s time to divide. These growth factors switch on antenna-like proteins, such as epidermal growth factor receptors (EGFRs), on the recipient cell. Once it’s been stimulated, an EGFR protein forwards the “divide now” message through a series of other molecules to AKT, which then sends it to other proteins that help orchestrate the cell’s separation into two cells. Because of their central position in the social network, AKT proteins take part in many of the cell’s fundamental decisions—not just whether to divide, but also how much to grow, whether to move, and even whether to die.
One way in which the AKT proteins promote cancer is through oversharing, sending out too many messages through the cellular network. This often occurs because cells accidentally make additional copies of one of the AKT genes. Melanoma tumors often carry extra copies of the AKT3 gene, for example, and so do some patients with triple-negative breast cancer, a variety of the disease that is hard to treat. Even if they are present in the right amounts, AKT proteins can dispatch too many signals if the proteins they interact with overstimulate them or if the proteins that normally inhibit them are faulty or absent.
Whatever the cause—oversharing, overstimulation, or lack of inhibition—a faulty AKT control circuit enables cancer cells to thwart one of our protections against tumors. Billions of our cells kill themselves every day, and it’s perfectly normal. They were worn-out or damaged, so they sacrificed themselves. Cancer cells have abnormalities in their DNA, but they often fail to press the self-destruct button. AKT proteins help cancer cells escape death by blocking two proteins that promote cellular suicide, in effect broadcasting a “stay alive” message.
In addition, AKT proteins are partly to blame for one of cancer’s most dangerous traits, the ability to spread. Cells often leave a tumor and travel to a new part of the body, founding a second tumor, or metastasis, in their new home. Most patients who die from cancer are killed by metastases, not by the original growths. Researchers have found that overactive AKT proteins stimulate metastasis in several cancer types, including colon cancer, breast cancer, and pancreatic cancer.
What is particularly challenging for researchers developing treatments is that AKT proteins can also stymie traditional cancer therapies. Radiation and chemotherapy kill abnormal tumor cells by injuring their DNA. But AKT proteins switch on mechanisms that mend the damage, allowing the cancer cells to survive. For instance, researchers have found that in a type of brain tumor known as glioblastoma, AKT3 protects cells against radiation and chemotherapy. Standard cancer treatments rarely work for glioblastomas, and AKT3’s shielding effect might explain why.
Given the AKT proteins’ role in cancer, “there’s tremendous interest” among researchers and pharmaceutical companies in developing drugs to counteract them, says Alex Toker, a cancer biologist at Harvard Medical School in Boston, Massachusetts, who studies the AKT family. So far, the FDA has approved only one AKT-blocking drug, miltefosine (whose trade name is Impavido), and it’s only useful for treating a type of parasitic infection. But that could soon change. Researchers have produced several compounds aimed at AKT proteins, and clinical trials are now testing some of them in cancer patients. For example, the drug GDC-0068 (also known as ipatasertib) is being tested against prostate cancer, triple-negative breast cancer, and other types of tumors. Likewise, clinical trials are assessing another drug, MK2206, for use against several kinds of tumors, including breast cancer and pancreatic cancer.