By Michael Irving

A promising new cancer drug will soon enter phase 2 clinical trials, after finding success in animal models and preliminary human studies. Known as AMG 510, the drug targets a gene mutation that’s one of the most common causes of cancer.

Errors in a gene called KRAS are responsible for up to 20 percent of human cancers, particularly leukemia, colorectal, lung and pancreatic cancers. That, of course, put it squarely in the sights of scientists – but unfortunately, effective treatments have eluded them until now.

The problem is that the KRAS protein is too smooth. Normally, proteins are pockmarked with little pockets on their surfaces, and drug molecules are designed to latch onto those in order to get to work. But KRAS appeared to have nowhere for drugs to get a foothold.

So researchers looked a little closer. A team from biotech company Amgen examined the proteins of a specific KRAS mutation, called KRAS(G12C), using X-ray crystallography at Berkeley Lab’s Advanced Light Source (ALS). This technique creates a high-resolution map of the structure of the protein – and sure enough, they found a tiny pocket that had been missed previously.

Later studies allowed the team to investigate molecular interactions and design drugs that would fit into this pocket. The end result of several years’ work is AMG 510, which binds to the pocket and locks the protein in an inactive state.

The KRAS(G12C) mutation is found in about 13 percent of lung adenocarcinomas, three percent of colorectal cancers and two percent of other solid tumors, meaning AMG 510 is a promising potential treatment for those diseases.

In earlier studies, the drug was shown to home in on KRAS(G12C) and effectively bind to it, causing tumors to shrink in mice. After these results, the US Food and Drug Administration (FDA) fast-tracked AMG 510 as a treatment for metastatic non-small cell lung cancer that had the KRAS(G12C) mutation and had previously eluded treatment by other means.

And now it’s been approved for phase 2 clinical trials. That makes AMG 510 the first therapy for this common cancer cause to reach clinical trials. Hopefully it bears fruit, and paves the way for the same discovery method to uncover new treatment possibilities for other hard-to-target mutations.

The results of the earlier studies were published a few months ago in the journal Nature.

Source: Lawrence Berkeley National Laboratory