The Story of NRAS


The Story of NRAS

NRAS mutations aren't just common in cancers; they drive tumors such as skin melanomas to grow.

NRAS Mutations at a Glance
  • Involved In: More than one third of cutaneous melanoma--the most common sort of skin cancer. Also found less frequently in acute myeloid leukemia and colorectal cancer, liver cancer, lung cancer, and thyroid cancer.

  • Testing requires: Tumor sample, preferably from a recent biopsy.

  • Prognosis: Recent studies suggest that melanoma with an NRAS mutation may have a poorer prognosis.

  • Treatment: Some cancer with NRAS mutations is resistant to ionizing radiation. No drugs directly target it, but some treatments aimed at related pathways, including combination therapies, may be useful.

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Whether it’s at the beach or simply hanging out in a backyard, too many summers soaking up the sun can damage skin with wrinkles, spots, and signs of age. For some, however, too much sun can also lead to a cancerous mole, one of the early insidious signs of a cutaneous melanoma.

Some aggressive forms of this melanoma carry a mutation in the NRAS gene, also known as the neuroblastoma RAS viral oncogene homolog. Much about this gene is packed into its little four letter name. NRAS was the third member of a gene family linked to human cancers, known as the RAS oncogenes. The first two RAS genes, KRAS and HRAS, were originally identified from cancer-causing viruses in rat sarcoma cells (hence the name RAS). In 1982, scientists at the Institute of Cancer Research in London linked a third RAS gene to cancer in neuroblastoma cells, which are derived from the nervous system, and named it NRAS.

All three human RAS genes are implicated in different kinds of cancer. KRAS mutations, for example, occur in approximately 36 percent of colorectal cancer cases. Despite being originally discovered in nervous system cells, NRAS is most frequently correlated with skin melanomas. It’s thought to occur in up to 35 percent of all cutaneous melanoma cases, and may be especially important in cancers caused by long hours of sun exposure. NRAS mutations are also thought to be present in most of the melanomas that start in moles people have had since birth. Mutated forms of NRAS are also seen in people with colorectal cancer, liver cancer, lung cancer, acute myeloid leukemia, and thyroid cancer. However, these cases are less frequent than those with melanoma.

When mutated, all three RAS oncogenes have the potential to “drive” cancer. Mutated NRAS is not just common in tumors – it’s essential for a cancer cell to survive and grow. How can a single gene mutation have such a massive impact?

The NRAS gene carries the code to make a protein also called NRAS. Much like the proteins made by its relatives KRAS and HRAS, the protein made by NRAS acts like a two-way switch. These molecular switches relay signals from outside the cell to pathways within, instructing cells to grow, divide, or move in specific patterns. RAS proteins are switched on when a small energy-storing molecule known as GTP binds to them. A small part of RAS works as an enzyme that breaks GTP into a smaller version known as GDP. When the GTP is cut down to GDP, the RAS protein gets turned off, and the pathways turned on by this switch also quiet down.

The mutant NRAS protein, however, made by a mutant version of its gene, fails to switch off. When it remains constantly active, the mutant instructs cells to grow and divide abnormally, leading to cancer. Mutations in the mutant NRAS protein, however, made by a mutant version of its gene, fails to switch off. When it remains constantly active, the mutant instructs cells to grow and divide abnormally, leading to cancer. Mutations in RAS genes are known to occur in approximately one-fifth of all human cancers. Can we pinpoint which tumors carry these mutations, and find a way to turn these switches off?

To start with, we need to find these mutation-carrying tumors. Many cutaneous melanomas carry either an NRAS mutation or a mutation in BRAF, another gene that can drive cells to proliferate. Both can be detected through genetic tests. Several manufacturers provide tests that can detect BRAF or NRAS mutations in melanoma tumor samples.

When the NRAS gene is mutated, it makes an abnormal NRAS protein that is too active. The abnormal NRAS protein instructs cells to grow and divide abnormally fast. This can cause cancer to develop.

NRAS or BRAF mutations can make a patient’s metastatic melanoma more complex when compared to a melanoma without either of these mutations. For example, tumors with BRAF mutations are likely to grow in size more quickly than those without a mutated BRAF gene. An NRAS mutation, however, can make for even more aggressive cancers. Recent studies have suggested that an NRAS mutation may be correlated with a poorer prognosis and shorter survival in stage IV melanoma.

There are no drugs at present that can specifically target mutated NRAS, unlike its buddy BRAF. But many existing treatments can dial down the cellular pathways that mutant NRAS keeps activated. Some such targets include the PI3K pathway, MAPK pathway and the MEK gene. MEK gene activity, for example, can be controlled by medicines such as trametinib and selumetinib.

Mutated NRAS may also alter how a tumor responds to treatment. It makes some cancers more resistant to ionizing radiation treatment or to drugs that target the EGFR gene. But patients with NRAS mutations are also likely to respond better to immune therapy for melanoma.

Recent studies also suggest that tumors with NRAS mutations may respond better to certain combinations of therapies, such as combining a MEK-targeted drug with immune inhibitors such as CDK4 and CDK6. In an early clinical trial completed in 2014, this therapy stopped tumor growth or caused melanomas to shrink in 19 out of 21 patients with NRAS-mutated melanomas. However, combination treatments such as this one are still in the early phases of being tested.

Scientists are still studying the other ways an NRAS-mutated melanoma behaves differently from melanoma with a BRAF mutation. For example, one study found that cancers with altered NRAS genes were more often seen in older people with chronic ultraviolet (UV) exposure, such as people who had spent more time in the sun without adequate protection. These cancers were more likely to be on patients’ limbs and extremities rather than the torso.

Overall, an NRAS mutation can make a cancer look and behave differently than melanomas with other gene mutations. But studies of the other RAS genes, including KRAS and HRAS, give scientists clues on how to target the actions of a mutant NRAS.

Both KRAS and NRAS, for example, place themselves at the edge of cells, with bits of their proteins sticking out on either side, in order to transmit external signals to molecules inside the cells. Scientists have designed molecules that can block a mutant KRAS protein from planting themselves in this way. In the near future, they may find a way to re-design such inhibitors to also act on mutant NRAS proteins.

NRAS mutations often pop up in drug-resistant melanomas. They’re also prime targets for different combinations of therapy. As personalized medicine advances, cancers with NRAS mutations may be treated with a unique combination of drugs for each patient. But figuring out precisely how an NRAS mutation changes a melanoma – where and when it forms, how it responds to treatment, and whether it influences prognosis – is a key first step to identifying the best way to treat each individual patient.

An NRAS mutation can be detected through genetic tests. There are several manufacturers of genetic tests that can detect NRAS mutations in melanoma tumor samples. Testing may be performed onsite at a medical facility or at a specialized laboratory. Ask your doctor which tests are appropriate for you.

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