This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Cell-communication molecules called kinases play a key role in the growth and spread of many cancers. But exactly which kinases are active in a particular cancer is not always clear—there are 1.8 million sites on human proteins that kinases might act on, and researchers have fully characterized fewer than 1% of them.
A Harvard Medical School team has now built an AI-enabled tool called KinoPlex that maps the three-dimensional structures and biochemical environments of all these sites and matches them with the specific kinases that can interact with them. In a paper published in Nature Biotechnology, the researchers demonstrate that KinoPlex can be used to determine which kinases are active in specific cancer cells. If validated in the clinic, the tool could help doctors identify which of around 100 existing kinase-inhibiting treatments would be most effective for a particular patient.
KinoPlex may also reveal targets for future cancer therapeutics. "Kinases are rapidly becoming one of the largest targeted families in therapeutics," said senior author Steven Gygi, professor of cell biology in the Blavatnik Institute at HMS. "By analyzing a patient's particular cancer, their particular set of mutations, their particular phosphorylation state, we might be able to predict which drugs would provide the best therapeutic effect." The researchers are partnering with oncologists at several hospitals, including Brigham and Women's Hospital and Massachusetts General Hospital, to test KinoPlex with clinical samples from cancer patients.
"We need really good diagnostic indicators for cancer, and this is very different from existing diagnostics—it's a signature of a process, not just a level of a protein or something similar," Gygi said. "I think it can be really useful." They have made KinoPlex publicly available with the help of Cell Signaling Technology, a life sciences company. "Everything that we've built is available to the scientific community," said first author David Vanderwall, a Harvard MD-Ph.D. student in the Gygi Lab.
"Anyone can start applying it to their work." Kinases work by attaching signaling molecules to different proteins, changing how those proteins behave. This process, called phosphorylation, controls cell growth, division, metabolism, DNA repair and other activity. Mutations in kinases can contribute to cancer and other diseases.
There are roughly 500 different kinases, and each has different requirements for its binding sites. Previous work, much of which was led by corresponding author Lewis Cantley, HMS professor of cell biology at Dana-Farber Cancer Institute, has focused on identifying the biochemical signatures at these sites to determine which kinases could be a match. KinoPlex is the first approach to also incorporate the 3D structures of these areas.
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