Targeting Oncogenic RAS in Pediatric Leukemia
One of the most deadly but un-drugged cancer-causing proteins is called RAS. RAS mutations are present in approximately 20% of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), 25% of juvenile myelomonocytic leukemia (JMML), and up to 50% of pediatric mixed lineage leukemia (MLL-ALL). Pediatric leukemias bearing RAS mutations are typically associated with resistance to cancer treatment and reduced overall survival. Therefore, new insights into the mechanisms of RAS regulation are urgently needed in order to guide drug development strategies. We have developed “stapled peptides” modeled after a protein domain that interacts with RAS proteins and discovered that our compounds can directly inhibit RAS by a new mechanism. In addition to dissociating a helper protein, called SOS1, from RAS, we surprisingly found that our stapled peptides can block RAS directly.
The purpose of this research is to apply chemical, structural and biological approaches to characterize this new mechanism of RAS blockade and, in doing so, advance a new therapeutic strategy for pediatric leukemia that overcomes RAS-driven treatment resistance.