Our understanding of the causes of cancer informs our efforts to develop effective therapies. Mutations of the BRAF gene that result in an aberrant KIAA1549-BRAF fusion protein and subsequent dysregulation of the RAS/RAF/MEK signaling pathway occur in a large number of pediatric low-grade gliomas. This pathway is therefore a good candidate pathway for therapeutic targeting. There are currently numerous clinical trials for many cancers that examine the effectiveness of small molecule inhibitors of the MEK kinases. Some MEK kinase inhibitors work better than others, but it is not clear why. Michael Eck, MD, PhD uses structural biology approaches to examine the physical interactions between MEK inhibitors and MEK kinases to determine what physical features affect bioactivity. This will help us design better candidate inhibitors.
In parallel work, Sara Buhrlage, PhD is spearheading an approach to circumvent the problem of drug resistance that frequently develops with prolonged drug treatments. While inhibited by drugs, oncogenic proteins often remain in cells and can contribute to additional cellular processes underlying resistance. An approach to circumvent this problem involves the selective degradation of oncogenic proteins. Ubiquitin mediated degradation is a fundamental cellular process. Designated proteins are “tagged” by ubiquitin ligases and consequently recognized and degraded by cellular proteolytic machinery. In opposition, deubiquitylating (DUB) enzymes remove ubiquitin tags countermanding degradation. Dr. Buhrlage’s lab is developing ways to manipulate this cellular system to selectively remove oncogenic drivers in transformed cells.
