Shubham Pant, MD, associate medical director of the Clinical & Translational Research Center, associate professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discusses targeting KRAS mutations in advanced or metastatic solid tumors.
An ongoing, phase 1 first-in-human trial (NCT04111458) is evaluating the novel pan-KRAS inhibitor BI 1701963, which binds to son of sevenless homolog 1 (SOS1), alone and in combination with the MEK inhibitor trametinib (Mekinist) in patients with advanced KRAS-mutated solid tumors.
Historically, KRAS was thought to be an undruggable target, Pant explains. However, targeting KRAS is an area of significant research, as KRAS mutations are present in multiple tumor types including lung cancer, colorectal cancer, cholangiocarcinoma, and pancreatic cancer.
Inhibiting SOS1 stops KRAS phosphorylation and prevents activation of the KRAS pathway. Ultimately, this may starve the tumor of its growth signal, explains Pant. Additionally, combining BI 1701963 with trametinib could block the RAS/RAF/MEK pathway to provide a more pronounced antitumor effect, concludes Pant.