Abstract
RAS mutations are observed in 20% of all cancers. RAS functions as a molecular switch that cycles between an inactive GDP-bound state and active GTP-bound state. Once activated RAS recruits’ effectors, such as RAF kinase, to the plasma membrane to activate the MAPK signaling pathway. Oncogenic mutants lock RAS in the active state resulting in chronic MAPK signaling and cellular proliferation. The KRAS isoform is highly mutated in colorectal, lung and pancreatic cancers which generally have poor patient outcomes. KRAS has historically been regarded as undruggable, however progress over the last 10 years has resulted in the approval of 2 clinical compounds for treating patients with KRAS-G12C mutations. These current drugs target inactive KRAS-G12C and prevent its activation but unfortunately patients develop resistance rapidly. In collaboration with BridgeBio Oncology Therapeutics, the RAS Initiative has developed as inhibitor (BBO-8520) that targets both the inactive and active forms of KRAS-G12C. BBO-8520 displays rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple mouse models. BBO8520 is currently in phase 1 clinical trials in patients with KRAS-G12C non-small cell lung cancer.
Mutations in RAS and the MAPK pathway also occur in a group of developmental disorders, collectively known as RASopathies. RIT1, a RAS family member, is mutated in the germline of Noonan Syndrome patients, which is a RASopathy disorder. Pathogenic RIT1 activates the MAPK pathway but by a non-canonical mechanism. We determined that activated RIT1 binds directly to RAF kinases but does not activate them. Rather it recruits RAF kinases to the same region of the plasma membrane where RAS resides, and RAS subsequently activates RAF. Inhibition of the MAPK pathway alleviates the Noonan syndrome phenotype in mouse models. These data shed light on the function of pathogenic RIT1 and possible approaches for therapeutic intervention.
About the Speaker
Andrew "Andy" Stephen
Senior Principal Scientist, Biochemistry/Biophysics Group, NCI RAS Initiative, Frederick National Laboratory for Cancer Research
Andy Stephen received his Ph.D. in biochemistry from the University of Liverpool in the UK. He then moved to Washington University in St Louis where he conducted his postdoctoral training investigating nuclear protein regulation by the ubiquitin/proteasome pathway. He completed further postdoctoral training at UCLA where he investigated the structure/function of vaults, a large ribonucleoprotein particle found in all cells, but whose function is in unknown. In 2000 he accepted a staff scientist position at the Frederick National Laboratory for Cancer Research in Frederick, MD where he collaborated with NCI investigators to characterize protein/protein and protein/small molecule interactions using a variety of biophysical methods. In 2013, the NCI established the RAS Initiative as a center to investigate new approaches to targeting RAS. Currently, as s senior principal scientist, he directs the RAS Biochemistry and Biophysics Lab. His group interrogates the biochemical activities of oncogenic mutant KRAS and develops screenable assays to identify small molecule inhibitors against KRAS. His research interests are directed towards the biophysical details of KRAS activation of signal transduction at the plasma membrane and its dysregulation in cancer and developmental disorders.