Editor's note: This is part one of a two-part series on receptor tyrosine kinases in cancer.
Hyperactivation of the pathways controlled by receptor tyrosine kinases, or RTKs, is a major mechanism of cancerous cell growth. Inhibiting such activation, in turn, has led to some of the major anticancer advances of the past few years: Avastin (bevacizumab, Genentech Inc.), Gleevec (imatinib, Novartis AG), Herceptin (trastuzumab, Genentech Inc.) and Tarceva (erlotinib, OSI Pharmaceuticals and Bayer Corp,) are just some of the cancer drugs that work on receptor tyrosine kinase pathways.
Met kinase is a member of the RTK family that appears ripe for clinical intervention. It is hyperactive in more than half of all solid tumors. That has not escaped the notice of either medical researchers or the biotech industry, since inhibiting Met kinase is an approach being tested in more than a dozen cancers. Compounds in development by biotech include AVEO Pharmaceuticals' AV-299 and Exelixis Pharmaceuticals' XL880, which is in clinical development for renal-cell carcinoma, gastric cancer and head and neck cancer.
In the Sept. 11, 2007 issue of the Proceedings of the National Academy of Sciences, researchers from the Van Andel Research Institute and the British Medical Research Centre Council's Laboratory of Molecular Biology reported on a potential addition to the anti-MET arsenal: a fragment of the natural binding protein, but tweaked to convert it from an activator to an inhibitor.
Met receptor's regular ligand is hepatocyte growth factor (or scatter factor, because it induces cells to scatter). As the authors pointed out in their paper, hepatocyte growth factor and other ligands "must have at least two functions, namely receptor binding and activation."
"With specific mutations, you can separate those two functions," senior author Eric Xu, a distinguished investigator at the Van Andel Research Institute, told BioWorld Today. "It is possible to retain the binding ability, but the mutated receptor now functions as an antagonist."
Xu and his team used a fragment of hepatocyte growth factor known as NK1 and first studied its binding characteristics to the Met receptor in vitro. They found that adding purified NK1 to Met receptor induced the receptors to pair up into dimers. Crystal structure studies suggested that NK1 does this by forming a dimer itself. When heparin is present, two molecules each of heparin, NK1 and Met appear to form a complex that allows Met to activate intracellular pathways.
The authors then mutated four key amino acids in the NK1 protein, either alone or in combination, to test whether they could achieve Met receptor binding without Met receptor activation. They found that while the mutants could bind both heparin and the Met receptor, most of them drastically reduced Met dimerization and activation, and three mutants abolished Met activation altogether. Cells treated with NK1 showed less DNA synthesis in response to full-length hepatocyte growth factor, and less activation of Met-dependent intracellular pathways.
Xu and his colleagues wrote in their PNAS paper that the results "provide important insights into the molecular mechanism of Met activation by NK1 and a rational basis for design and optimization of Met antagonists for cancer therapy."
On the basic science side, the research offered clues to how the MET receptor dimerizes. The most likely course of events is that HGF dimerizes first, and brings MET monomers together by binding them.
On the clinical development side, Xu said that "receptor dimerization has been proposed as a common mechanism of activation." For that reason, the approach of using endogenous proteins "may be applicable to all RTKs." Xu said that among his group's research plans are to test NK1 in animal studies, and to "extend our ideas to other [RTK] receptors."
Xu believes that if the approach works, it has advantages over both small molecule and other protein drugs. Small molecules, the authors wrote in their paper, have "limited bioavailability and specificity." As for the comparison to protein drugs, NK1 is much smaller than other protein drugs such as antibodies and decoy receptors. Xu also pointed out that "NK1 is an endogenous protein," which means that the body is unlikely to have an immune reaction to it as a cancer therapy. "That is what is particularly exciting about this approach," he noted.