A research team led by Joseph Schlessinger, Ph.D., the William H. Prusoff Professor and chair of pharmacology, has solved the atomic-level structures for active and inactive forms of a protein segment implicated in several types of cancer, opening up a new set of molecular targets for cancer therapies.
The results, reported in the July 27 issue of Cell, highlighted previously unidentified changes in the protein’s structure that seem to be crucial for its activation. “It gives us totally new avenues for developing drugs for a large group of target proteins that are responsible for several cancers,” Schlessinger said.
The study focused on one of 59 receptor tyrosine kinases (RTKs), a set of related proteins whose activities have long been linked with cancer. Normally, RTKs become active only under particular circumstances in order to help cells proliferate, differentiate and survive. But certain mutations in RTKs can turn on the proteins inappropriately, causing aberrant cell proliferation that may lead to cancer. Blocking the activities of RTKs has become a major strategy in anticancer drug design.
Two recently developed and highly successful cancer-fighting drugs, Gleevec and Sutent, work in this way. Gleevec is effective against some stomach cancers and leukemias; Sutent works against stomach and some kidney cancers. But Schlessinger, who helped discover Sutent, said many cancers don’t respond to Gleevec or Sutent and those that do develop resistance to the drugs.
Schlessinger’s laboratory has spent the last 10 years assembling an atomic-level view of the extracellular domain of an RTK called Kit. By comparing the structure of the protein segment (representing Kit in its inactive state) with that of the active form, his research group has identified changes in Kit that are important in understanding its activation.
The results suggest that in their active state Kit molecules change their shape such that certain portions of the extracellular domain in one Kit molecule move close enough to interact with their counterparts on the other Kit molecule. Schlessinger and colleagues have also provided evidence that these previously unidentified interactions are required for Kit activation, and mutations predicted to strengthen the interactions are known to contribute to various forms of cancer.
Since Kit is part of a family of RTKs with similar extracellular domains, the targets represented by this study probably exist in more than a half-dozen other RTKs that have been implicated in various cancers. “It’s a mechanism that is likely to be universal to quite a few of these RTKs,” Schlessinger said.
Drugs aimed at these new targets might be effective against Gleevec- and Sutent-resistant cancers, offering hope to many cancer patients who are trying to stay one step ahead of the enemy.