Drug resistance occurs in the majority of targeted kinase inhibitor therapies. One mechanism by which tumor cells bypass kinase inhibitor treatment is through kinome reprogramming, a process characterized by system-wide changes in kinase signaling networks. Development of combination therapies that anticipate tumor adaptive responses to kinase inhibitor treatments will be essential for long-term clinical benefit. We have designed a unique proteomic approach combining mass spectrometry and protein kinase-capture beads that globally measures kinase activity allowing the study of kinome dynamics. Overall, the goals of our research are to utilize this innovative approach to assess global kinome behavior and its response to small molecule inhibitors to identify previously undiscovered kinase targets leading to new and effective combination therapies to treat cancer. Our lab currently has two focused projects including;

Project 1. Unlocking the therapeutic potential of the untargeted kinome. Protein kinases represent one of the most tractable drug targets in the pursuit of new and effective cancer treatments. However, the majority of these kinase-specific inhibitors target a relatively small fraction of the human kinome. Of the 518 human protein kinases, only 42 (8%) are currently being explored as primary targets for drug therapy. Thus, greater than 90% of the kinome remains unexplored or “untargeted” for drug therapy. In the proposed studies, we will utilize our novel kinome profiling technology to identify previously unexplored kinases to be evaluated as new therapeutic targets for the treatment of cancer.

Project 2. Designing combination therapies for MEK and/or PI3K inhibitors in PI3K/RAS altered cancers. Altered PI3K/RAS signaling has been observed in many cancers including ovarian and colon cancer. Using our novel mass spectrometry approach that globally measures kinase activity, we are interested in defining kinase targets driving tumor survival and MEK and/or PI3K inhibitor resistance in ovarian and colon cancer models. These discoveries will facilitate the design of new clinical trials involving MEK and/or PI3K inhibitor combination therapies for PI3K/RAS altered cancers.