Hopeful progress on cancer scourge

Scientists report gains against Death Star

After 40 years of effort, researchers have finally succeeded in switching off one of the most common cancercausing genetic mutations in the human body. The finding promises to improve treatment for thousands of patients with lung and colorectal cancer, and may point the way to a new generation of drugs for cancers that resist treatment.

The finding has already led to a new medication, sotorasib, by drugmaker Amgen. Other companies are close behind with their own versions.

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

The new drug attacks a cancercausing mutation, known as KRAS G12C, that occurs in 13% of these patients, almost all of whom are current or former smokers. Sotorasib made the cancers shrink significantly in patients with the mutation, Amgen reported last week at the World Conference on Lung Cancer.

On average, tumors in the patients stopped growing for seven months. In three out of 126 patients, the drug seems to have made the cancer disappear entirely, at least so far, although side effects included diarrhea, nausea and fatigue.

It already is routine to test lung cancer patients for the mutation, because they are often resistant to other drugs, said Dr. John Minna, a lung cancer specialist at the University of Texas Southwestern Medical Center in Dallas.

How the offswitch was discovered is a story of serendipity and persistence by an academic chemist who managed the seemingly impossible.

In 2008, that chemist, Kevan Shokat, a professor at UC San Francisco, decided to focus on the mutated gene. It had been discovered 30 years earlier in rats with sarcomas, a type of cancer that begins in bones and soft tissues.

The search for drugs to block previously discovered cancercausing mutations was always straightforward: Researchers had to find a molecule that attached to the mutated protein and could stop it from functioning. That strategy worked for kinase inhibitors, which also block a protein created by gene mutations.

KRAS was different. The gene directs production of a protein that normally flexes and relaxes thousands of times a second, as if it is panting. In one position, the protein signals cells to grow; in the other, it stops the growth. With the KRAS mutation, the protein remains mostly in an “on” position, and cells are constantly forced to grow.

“Our medicinal chemists referred to it as the Death Star,” said Dr. David Reese, executive vice president for research and development at Amgen.

Shokat and his colleagues began looking for a molecule that could do the trick. Five years later, after screening 500 molecules, they found one. Their drug held the protein steady.

Lung cancer is only the beginning, Shokat said. The next challenge is pancreatic cancer, one of the most lethal types: “KRAS is the signature mutation for pancreatic cancer,” he added.

Most patients have such a mutation, and while it makes the disease very difficult to treat, now it may also make the cancer particularly vulnerable. Researchers have already found drugs that seem promising.