The Story of HRAS


The Story of HRAS

A gene discovered in rats has positive implications for many patients with bladder cancer.

HRAS Mutations at a Glance
  • HRAS mutations are common in bladder cancer, head and neck squamous cell carcinoma, and other cancers. Studies suggest HRAS mutations may be common in thyroid and kidney cancers.

  • HRAS is part of a family of RAS genes that also includes KRAS and NRAS. Taken together, the RAS genes are some of the most commonly mutated genes in human cancer.

  • In healthy cells, HRAS moves messages for the cell to divide between cell membrane and nucleus. When mutated, HRAS may pass this message along too frequently, leading to cancer.

  • Testing for an HRAS mutation requires a tumor sample, ideally one taken during a recent biopsy.

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This gene is also known as:


The story of HRAS—as with many genes implicated in cancer—begins with viruses. In 1964, a researcher named Jennifer Harvey figured out how to give rats cancer by injecting them with a virus isolated from a rat with leukemia. The rats quickly developed tumors around their injection sites. But just because viruses caused cancer in rats didn’t necessarily mean they would in humans, and so, in the late 1970s, Boston researchers Mark Weinberg and Chiaho Shih decided to go after the DNA of human cancer.

The pair took some cells of human bladder cancer, isolated the DNA, and cut it into fragments that they then inserted into healthy cells in dishes. Soon, some of those cells began to proliferate. By 1982 they—and two other groups of researchers—had isolated the piece of DNA that caused this proliferation, uncovering a gene from the RAS family that had also been isolated from cancer-causing viruses in mouse cell lines. They named it HRAS, for “Harvey rat sarcoma viral oncogene homolog,” because the cellular DNA present in the human tumors was similar to the relevant part of the rat virus discovered by Harvey. HRAS is a human gene involved in the cell cycle that is commonly mutated in bladder and other cancers.

In order to understand the role that HRAS plays in the development of cancer, it’s necessary to understand some more about how cancer works. All cancer begins as an error in DNA. Over time, errors accumulate, which can lead to unchecked cell growth. In healthy cells, DNA is self-regulating. It tells cells when to divide, how many times, and when to stop dividing. In the last few decades, researchers have discovered two categories of genes that help regulate this process—oncogenes (including HRAS), a sort of accelerator pedal on cell replication, and tumor suppressors, which function as the brakes. When these segments of DNA go wonky due to mutations, a cell can end up with an accelerator permanently stuck to the floor, or a brake that just doesn’t work, or both.

HRAS is an oncogene. In a healthy cell, it produces a protein, H-RAS, that ferries signals between the cell membrane and the cell nucleus that encourage the cell to divide. When HRAS becomes mutated, the proteins it produces don’t do their work as they should, which, when combined with the effects of other cellular mutations, can lead cells to divide uncontrollably, producing cancer in patients.

HRAS has some siblings—KRAS and NRAS—that perform similar functions within the cell. Taken together, this family of RAS genes are some of the most commonly mutated oncogenes in human cancer. About 33 percent of all tumors exhibit a mutation in a RAS gene, although of the three siblings, HRAS is the least common, occurring in only about 3.3 percent of cancer.

The mutations that lead to cancer may be acquired over time during errors in cell replication, through environmental exposure, and more, and in some cases, cancer-risk-raising mutations are inherited or otherwise built into bodily DNA.

Most HRAS mutations in cancer have been acquired over time. Acquired HRAS mutations are most commonly found in bladder, thyroid, and kidney cancers, as well as head and neck squamous cell carcinoma.

So far, medical efforts to directly target mutations such as the HRAS mutation have not been successful, although there have been some promising leads and workarounds. HRAS and other genes of the RAS family are part of interlocked chains of events inside the cell called pathways. You can think of a pathway like a line of dominos stacked on end. Pushing the first domino over causes a chain reaction. Pathways in cells are considerably more complicated, though—they resemble complex webs of dominos rather than a single line. If cellular pathways were railroads, proteins such as H-RAS would sit at some of the hubs, controlling the direction of cellular processes. H-RAS is part of a pathway that includes the proteins MEK and ERK farther downstream.

Pathways like this present “druggable targets”—opportunities for intervention with pharmaceuticals. The hope is that by identifying where cellular pathways start to go off the rails, researchers can create therapies that target just those locations. There is some good evidence that RAS mutations are crucial to helping tumors thrive, and that suppressing the function of RAS mutations can make tumors regress. But more research is needed.

Dr. Adrienne Cox is an associate professor of radiation oncology at the University of North Carolina who is researching the function of RAS genes and proteins. As she put it, “RAS itself is really hard to inhibit directly.” For this reason, for years researchers turned to targets downstream in the RAS-RAF-MEK-ERK pathway. If a tumor were a corporation, it’d be best to take it down by removing the CEO, but if the CEO was untouchable, it would make sense to start going after the VP of product instead, she explained. In the same way, since scientists had so much trouble going after RAS, they went after proteins farther down the chain instead. However, thanks to new technology and new understandings of how RAS works, attention is again turning toward finding ways to target RAS genes directly.

One of the challenges of working with RAS mutations within tumors is that cancer is sneaky. As Cox put it, “targeted therapies can work super well for a while, but resistance [to such drugs] arises within months, very often, and then you need to do something else.” For this reason, research focus is on combinations of drugs that might be able to be effective for longer in preventing or overcoming resistances that occur within cancer. Some drugs from a class known as farnesyl transferase inhibitors (FTIs) may be effective in blocking HRAS function in some tumors, particularly in tumors with an HRAS driver mutation.

A driver mutation, as distinct from a passenger mutation, Cox said, relates to a gene’s importance in the functioning of a tumor. Cancerous tumors carry many different mutations, but some are critical to the growth of the tumor while others are not. Which mutations are vital depends on the type of tumor and the unique combination of mutations in a patient. Think of a tumor as being like a car—the engine and wheels are more vital to its function than the rear view mirrors and paint color. In one patient’s tumor, HRAS might have the function of wheels, while in another it’s merely the hood ornament. Whether drugs such as FTIs are able to help a given patient depends on the unique makeup of that person’s tumor. And although the current wave of research has shifted away from targeting HRAS in favor of its more frequently occurring siblings KRAS and NRAS, patients with HRAS mutations still have many options for treatment. For example, in general, bladder cancer with HRAS is lower-grade and well treated by current therapies, Cox said.

Dr. William Y. Kim is a practicing oncologist specializing in kidney and bladder cancers, who also conducts clinical research on the genetics of cancer at his lab at the University of North Carolina. In Kim’s opinion, “having an HRAS mutation in bladder cancer is not useful for your clinical planning.” Given the science right now, the presence of an HRAS mutation doesn’t mean a patient will do better or worse, and as Kim put it, “we don’t think it can tell us what drugs to use in a patient with bladder cancer.” However, the presence of an HRAS mutation is fascinating to scientists.

As Kim put it, “there are two major flavors of bladder cancer—one is a high-grade tumor and one is a low-grade tumor.” Cells from high-grade tumors look more abnormal under a microscope and are more likely to grow and spread. About 70 percent of bladder tumors are low-grade at the time they are diagnosed and 30 percent are high-grade, Kim said. Some low-grade tumors will become high-grade over time, though. HRAS mutations are associated with low-grade tumors. And so, “if we find a high-grade tumor that has an HRAS mutation, then we know it began as a low-grade tumor and then transformed to a high-grade tumor. I’d say that’s of major scientific relevance,” Kim said.

What began as Jennifer Harvey’s inquiry into rat viruses ended up teaching researchers plenty about cancer and how it functions. That journey continues today as scientists dedicate themselves to unraveling the complex functions of RAS genes and how they interact with other crucial pieces of DNA. Hopefully, this research will uncover even more details about how cancer grows and develops, and benefit patients in the form of new pharmaceuticals and predictive information about how their cancer will develop.

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