Our Research

We use biochemical and structural methods (primarily X-ray crystallography & Cryo EM) to study the structure and regulation of kinases that are important in cancer. We are especially interested in understanding how cancer-causing mutations lead to loss of normal kinase regulation and in using structural approaches to develop new anticancer drugs. Active areas of investigation include: (1) lung cancer-derived mutations in the epidermal growth factor receptor (EGFR), (2) the structure and regulation of JAK-family kinases and their interactions with cytokine receptors, (3) regulatory circuitry of the MAP kinase pathway.

RAS, RAF, and Signaling Through the MAP Kinase Pathway

Understanding the structural basis for signaling through the RAS/MAP kinase pathway is a major area of interest in the lab. This pathway is central to control of cellular proliferation, differentiation and survival and is the most frequently mutated pathway in human cancers. RAF family kinases (ARAF, BRAF and CRAF) act as RAS-activated switches to control downstream signaling to MEK and ERK. Together, these three kinases constitute the MAP kinase cascade. We have determined structures of complexes of RAFs and MEK together with14-3-3 proteins that explain how the RAF/MEK/14-3-3 complex can be maintained in either an autoinhibited monomeric configuration or active dimeric configuration in phosphorylation-dependent manner. Structures with KRAS have yielded insights into the mechanism by which KRAS-driven recruitment to the membrane effects the switch between these two states.

In our ongoing studies, we are working to understand differences in regulation of the three RAF isoforms and to develop novel approaches to inhibiting the pathway in a more cancer-selective manner. Because the pathway is essential in normal cells throughout the body, existing drugs that indiscriminately block all signaling are poorly tolerated. The ideal therapeutic would block the mutated/altered RAF protein in cancer cells, while sparing the normal protein in healthy tissues. We are working to develop strategies toward this goal for pediatric low-grade gliomas that are driven by KIAA1549:BRAF, an oncogenic translocation/fusion with BRAF that is a major cause of this cancer, and by BRAF-V600E, a point mutation that is a frequent cause of malignant melanoma and other cancers including pediatric gliomas.

​Epidermal Growth Factor Receptor

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor are a major cause of non-small cell lung cancer. We have elucidated the mechanisms by which many of these mutations lead to constitutive ligand-independent activation of the receptor, as well as mechanisms of differential inhibitor sensitivity and acquired resistance. Guided by our structural and enzyme kinetic findings, with our collaborators we developed the first mutant-selective irreversible EGFR inhibitors active against the T790M resistance mutation. Several such agents whose development in the pharmaceutical sector was directly inspired and informed by our work are now showing efficacy in clinical trials, and one (osimertinib) has recently received FDA approval. Most recently, we have developed a first-in-class mutant-selective allosteric inhibitor of EGFR L858R/T790M and L858R/T790M/C797S.

​JAK Family Kinases

We have a long-standing interest in the regulation of JAK family kinases and their dysregulation in myeloproliferative neoplasms (MPNs).  We reported the first structure of a JAK kinase domain (that of JAK3), which enabled inhibitor development. Our studies of the JAK1 pseudokinase domain revealed a concerted conformational switch involving the V658F activating mutation (equivalent to V617F in JAK2) and an SH2-pseudokinase linker segment that is also the site of mutations in MPNs. We are currently working to understand JAK auto-regulation and mechanisms of cytokine receptor recognition with a focus on full-length JAK2.