The Westover lab is developing new cancer therapies by working at the intersection of biochemistry, structural biology, chemical biology, and medicinal chemistry to understand and manipulate cancer biology. Our fight against cancer is a team effort - Westover lab members collaborate extensively with each other and with other labs to accelerate cancer research and move projects forward. We focus on common drivers of cancer, targeting these with small molecules using innovative approaches. Our goal is to produce new cancer drugs and train outstanding scientists.
Large-scale tumor DNA sequencing campaigns have shown that activating RAS mutations are among the most common drivers of cancer. It is, therefore, not surprising that RAS sits at the epicenter of multiple signal transduction pathways that control cell survival and growth. A primary working hypothesis in our lab is that not all RAS mutations function in the same way and that mutation-specific tailored strategies will be required. To this end we are determined to characterize and understand the unique properties of specific mutant RAS isoforms. So far our work has shed new light on how KRAS G13D, a major cause of colorectal cancer, becomes activated and provided rationale for new treatment strategies to address other RAS mutations (MCR, 2015). In a related effort we are developing small molecule inhibitors for KRAS G12C, the most common RAS mutation in lung cancer. RAS signaling is contingent upon RAS binding to GTP. Designing small-molecules that compete for the GTP-binding site may seem like an obvious approach but it is technically challenging because RAS binds GTP with extremely high affinity. We hypothesized that irreversible chemistry would allow small molecules to effectively compete with GTP and, together with a number of collaborators, developed the first example of a GTP-competitive, covalent RAS inhibitors by specifically targeting the KRAS G12C mutation (Angew Chem Int Ed Engl. 2014; PNAS, 2014). Current research aims to optimize KRAS G12C inhibitors for biological study and cancer therapy.
Kinases regulate all manner of cellular processes including growth, division, motility and survival by moving phosphates from ATP to other molecules. Similar to RAS, genetic alterations of kinases are found frequently in tumors but, different than RAS, spectacular advances in personalized cancer therapy have resulted from development of small-molecule inhibitors. Standing on the shoulders of giants we apply lessons from of previous generations of kinase inhibitors to cancer-associated kinases for which chemical probes are not yet available. Our collaborative team has successfully developed inhibitors for the following targets: mTOR, a master regulator of metabolism (Cancer Res 2013); TAK1, an Achilles heel of some RAS-driven cancers (J Med Chem, 2014); and HER3, a pseudokinase involved in cancer progression and drug resistance (Nat Chem Biol 2014). We anticipate that further development of current lead compounds and future development of new inhibitors targeting other cancer-associated kinases will result in important biological discoveries and new cancer therapies.