Two new drugs finally hit ‘undruggable’ cancer target, providing hope for treatments

Cancer researchers are making progress toward a goal that has eluded them for more than 30 years: shrinking tumors by shutting off a protein called KRAS that drives growth in many cancer types. A new type of drug aimed at KRAS made tumors disappear in mice and shrank tumors in lung cancer patients, two companies report in papers published this week.

It’s not yet clear whether the drugs will extend patients’ lives, but the results are generating a wave of excitement. And one company, Amgen, reports an unexpected bonus: Its drug also appears to stimulate the immune system to attack tumors, suggesting it could be even more powerful if paired with widely available immunotherapy treatments. “This is a nice demonstration that [a combination of drugs] might actually work,” says KRAS researcher Channing Der of the University of North Carolina in Chapel Hill.

KRAS is one of three genes in the RAS family (for rat sarcoma) that produce proteins controlling an on-off switch for cell growth; mutated forms of these genes are found in about 25% of all cancers. But RAS proteins have been considered “undruggable,” in part because their smooth surfaces offer no obvious pockets to target with a drug. In 2013, however, chemical biologist Kevan Shokat’s lab at the University of California, San Francisco, identified a small molecule that could slip into a groove on a KRAS mutant called G12C (for a glycine mutated to a cysteine at position 12). The mutant is present in about 13% of the most common lung tumors, 3% of colorectal cancers, and 2% of other solid tumors. A company called Wellspring Biosciences later showed that when given to mice implanted with KRAS(G12C)-carrying human tumors, an improved version of Shokat’s molecule shrank the growths.

Amgen’s drug, AMG510, targets a second groove in the same KRAS protein. That appears to make it more potent and specific than Wellspring’s compound, the company reports this week in Nature. After mice with several types of tumors with KRAS(G12C) were given sufficient doses of the drug alone or in combination with other drugs, most tumors shrank or even disappeared.

Amgen also describes early results from the first human trial of a KRAS inhibitor, finding its drug partially shrank tumors in two of four patients with advanced lung cancer after 6 weeks of treatment. In meetings this year the company also reported that tumors regressed in about half of a larger group of 13 lung cancer patients. (Early results for colon cancer aren’t as encouraging; only one of 12 patients has responded. But “that was expected,” says Amgen director of research Jude Canon in Thousand Oaks, California, because colon cancer is more biologically complex and may require drug combinations.)

A second company, Mirati, also reported promising human results this week at a meeting and in a paper in Cancer Discovery. Its KRAS(G12C) inhibitor shrank tumors in three of six lung cancer patients, as well as in one of four colon cancer patients.

Besides blocking the KRAS(G12C) protein, the Amgen drug stimulates immune cells called T cells to attack the tumor, the researchers report. When AMG510 was combined with a drug called a PD-1 inhibitor that removes a brake on T cells, tumors vanished for good in nine of 10 mice. PD-1 inhibitors alone can eliminate some cancers, but most patients don’t respond. The results suggest “cures may be possible” if PD-1 drugs are given together with Amgen’s KRAS drug, Canon says. (Amgen has already begun to test this drug combination in cancer patients.) Although it’s not the first targeted cancer drug that stimulates the tumor microenvironment to attract T cells, “it’s nice to see it,” says cancer biologist David Tuveson of Cold Spring Harbor Laboratory in New York.

The new results are an “encouraging” step toward “a clinically effective [KRAS] inhibitor,” says Harold Varmus of Weill Cornell Medicine in New York City, who launched the RAS Initiative, an effort to target those proteins, in 2013, when he was head of the National Cancer Institute. “It’s an impetus for the rest of the field” to keep going, Tuveson says.

Der, who consults for Mirati, cautions that because tumors will likely develop resistance to these KRAS inhibitors, patients will undoubtedly need drug combinations. Still, says Der, who was among those who discovered RAS’s role in cancer in 1982, “I’m excited about these inhibitors. Having been in this field so long, a glimmer of hope is great.”

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