A promising new cancer drug that targets tumors caused by mutations in the KRAS gene – among the most common causes of cancer – is entering phase 2 clinical trials. It just passed phase 1 with excellent safety and efficacy results in animal models and promising ones in preliminary human studies. The drug – known as AMG 510 – was developed by Amgen. It’s the first therapy that inhibits a mutant KRAS protein to reach clinical trials.
The KRAS gene encodes a crucial cell signaling protein. Errors in the KRAS gene result in a mutant gene that causes cancer. AMG 510 inhibits a particular KRAS mutant called KRAS (G12C), which is present in about 13% of lung adenocarcinomas, 3% of colorectal cancers, and 2% of other solid tumors. Overall, errors in the KRAS gene are responsible for up to 20% of cancers, particularly leukemia, lung, colorectal, and pancreatic cancers. The research was published in the journal Nature.
Despite how common the KRAS mutation is in the pathogenesis of cancer, scientists haven’t been able to design a drug that could fight it because the surface of the protein is too smooth. There are no distinct regions on its surface where a drug molecule could bind. Usually, proteins are covered with pockets on their exterior, and drug molecules are designed to latch onto them.
So, the biotech company’s team of researchers used X-ray crystallography at Berkeley Lab’s Advanced Light Source facility to examine the protein of KRAS (G12C) in ultra-high resolution. The technique works by creating a high-resolution map of the structure of the protein. This is how the team made the breakthrough discovery of a small pocket on the molecule.
Analyzing the data and taking the study a step further by investigating the molecular interactions between KRAS (G12C) and potential inhibiting compounds that bind in this pocket, the scientists were able to design drugs that could fit into the pocket. The final result after a multi-year drug agent optimization program was a drug that could bind to the pocket and lock the protein in an inactive state.
The drug effectively caused tumors to shrink in earlier studies on mice. The results were so good that 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 if previous therapies didn’t work. Shortly after, the FDA approved it for phase 2 clinical trials. AMG 510 is the first therapy for this common cancer cause to reach clinical trials.
