Piro Lito

Piro Lito, MD, PhD is the Enid A Haupt Chair in Therapeutic Research and the Director of Basic and Translational Research in the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center. Lito has made several key advances in the effort to better understand and therapeutically target KRAS driven cancers. KRAS mutants were historically viewed as being undruggable and locked in an active state due to an inability to hydrolyze GTP.  He found that these mutants cycle between their active and inactive states in cancer cells (Science, 2016) and that their ability to hydrolyze GTP is enhanced by atypical GTPase activating proteins (Science, 2021). Through these studies he described the mechanism affording inactive state selective trapping of KRAS G12C and established a conceptual framework for subsequent therapeutic development and clinical trials.

Lito also helped develop and characterize pan KRAS inhibitors, which target a broad range of KRAS mutants found in cancer (Nature, 2023) and a mechanism targeting the active state of mutant KRAS (Science, 2023). More recently, he identified an approach that restores GTP hydrolysis by mutant RAS, thus repairing the defect caused by cancer mutations (Nature, 2024). This builds on his foundational work showing that some of these mutants rely on atypical GAPs for inactivation and addresses the longstanding challenge of pharmacologically reactivating RAS’s hydrolase function. Lito co-led the first-in-human KRAS G12C inhibitor clinical trial (NEJM, 2020), work that paved the way for the FDA approval of sotorasib for the treatment of patients with lung cancer — the first KRAS directed therapy to be approved in the 40 years since the discovery of KRAS mutations in patients. His work has also identified how tumors adapt to therapy (Nature, 2020) and genetic alterations leading to resistance (Nature, 2021).

These contributions have been recognized with the Trailblazer Prize for Clinician Scientists by the foundation of the National Institutes of Health and the Seldin-Smith Award for Pioneering Research by the American Society for Clinical Investigation