RAS Biology and Tri-Complex Inhibition

For decades, small molecules could not directly target RAS, the primary oncogenic driver of pancreatic cancer. Tanios S. Bekaii-Saab, MD, opens this discussion on metastatic pancreatic ductal adenocarcinoma by asking what changed. Anne Noonan, MB BCh, PhD, credits the 2013 discovery of a drug-binding pocket on the surface of mutant RAS, known as the switch II pocket, which enabled the first preclinical RAS inhibitors. She explains that RAS proteins cycle between an inactive guanosine diphosphate-bound off state and an active guanosine triphosphate-bound on state, and that oncogenic mutations shift this equilibrium toward the on state. Paul E. Oberstein, MD, describes the tri-complex approach: the oral drug enters the cell, binds the chaperone protein cyclophilin A, and that complex then binds active RAS to block downstream signaling, using the cell's own machinery. Shiraj Sen, MD, PhD, shares how he explains this mechanism to patients, comparing the medicine to a Trojan horse that uses a chaperone protein to reach and block RAS.