How Scientists Dropped Canker’s ‘Death Star’

    After 40 years of effort, researchers have finally succeeded in closing one of the most common cancer-causing genetic mutations in the human body. This discovery promises to improve treatment for thousands of patients with lung and colorectal cancer, and may guide the new generation of drugs to treat cancer.

    Drug manufacturer Amgen has already detected a new drug sotorasib. Other companies lag behind with their own versions.

    Amgen tested its drug in patients with the most common type of lung cancer, known as non-small cell cancer. The disease is diagnosed in 228,000 Americans a year, and for most patients in advanced stages, there is no cure.

    The new drug attacks a cancer-causing mutation, known as KRAS G12C, in 13 percent of these patients, almost all of whom are current or former smokers. Sotorasib significantly reduced cancer in patients with mutations, Amgen reported at the World Conference on Lung Cancer last week.

    On average, tumors in patients stopped growing for seven months. In three of 126 patients, the drug has completely disappeared the cancer, at least for now, although side effects include diarrhea, nausea, and fatigue.

    It is already routine to test lung cancer patients for mutations, as they are often resistant to other drugs, Drs. Said John Manna, a lung cancer specialist at the University of Texas Southwestern Medical Center in Dallas.

    Dr. Dana-Farber Cancer Institute Chief Clinical Research Officer in Boston, Drs. Bruce Johnson said that like some new cancer drugs, Amgen’s drug is not very effective. But in combination with other drugs, which target specific mutations, can alter the course of the disease in many patients.

    For example, at first the drugs targeting specific mutations in melanoma patients seemed meaningless, but when combined with other drugs, they eventually changed the prospects for patients with this fatal disease.

    “The more I saw it, the more optimistic I became,” Dr. Johnson said about Amgen’s new data.

    While KRAS G12C mutation is the most common in lung cancer, it also occurs in other cancers, particularly in colorectal cancer, where it is found in up to 3 percent of tumors and especially in pancreatic cancer. Some type of KRAS mutation is present in 90 percent of pancreatic tumors.

    How Off-Switch was discovered is a story of continuity and persistence by an academic chemist, which seems impossible.

    In 2008, that chemist, Kevan Shokat, a professor at the University of California, San Francisco, decided to focus on the mutated gene. It was discovered 30 years ago in mice with sarcoma, a type of cancer that begins in bones and soft tissues.

    Researchers found the mutation in human tumor cells, and then discovered that it was one of the most frequently mutated genes in many types of cancer. Different cancers spring from different mutations in the KRAS gene and the protein that encodes it. The G12C mutation occurs mostly in lung cancer.

    The search for drugs to prevent previously discovered cancer-causing mutations was always straightforward: researchers had to find a molecule that binds to the mutated protein and prevent it from functioning. That strategy worked for so-called kinase inhibitors, which also block proteins produced by gene mutations. There are now 50 approved kinase inhibitors on the market.

    KRAS was different. The gene directs the production of a protein that normally flexes and relaxes thousands of times in an instant, as if it is panting. In one case, the protein signals cells to grow; In another, it inhibits growth. With KRAS mutations, the protein remains mostly in the “on” state, and cells are forced to grow continuously.

    The standard solution would be a drug that would hold the mutated protein in the “closed” state. But it seemed impossible. The protein is large and spherical, and does not have deep pockets or cracks on its surface, where a drug may slip. It was like trying to drive a nail into a ball of solid ice.

    “Our medicinal chemists refer to it as the Death Star,” Dr. Said David Reese, executive vice president of research and development at Amazon. “It was very easy.”

    Hence Dr. Shokat and his colleagues began searching for a molecule that could. Five years later, after investigating 500 molecules, he made a discovery and found out why it works.

    His drug keeps the protein stable, causing a crack to appear on its surface. Dr. “We never saw that pocket before,” said Shaukat. The protein flexes normally and relaxes so quickly that it was almost impossible to see the narrow groove.

    And there was good news. The drug itself is associated with cysteine, an amino acid that occurs only in grooves due to the KRAS mutation. The drug only works against mutated proteins, and therefore only against cancer cells.

    “It’s really specific,” Dr. Shokat said. “this is amazing.” He His findings were published in 2013, causing a sensation in the area.

    Dr. of Amgen. Reese said the data provided us with evidence that we could actually do so, “and that” it silenced many. “

    Dr. Shokat also began working on a drug, now being developed by Johnson & Johnson. At least eight companies have their own KRAS inhibitors in clinical trials.

    Lung cancer is only the beginning, Drs. Shaukat said. The next challenge is pancreatic cancer, one of the deadliest types: “KRAS is a signature mutation for pancreatic cancer,” he said.

    Mutations occur in most patients, and when the disease becomes very difficult to treat, it can now make cancer particularly vulnerable. Researchers have already found drugs that look promising.

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