Piro Lito, M.D., Ph.D.

Research

The Lito lab investigates the properties of oncoproteins that drive cancer cell growth, with a focus on cancers driven by RAS mutations. RAS mutants were historically thought to be locked in an active state because of an inability to break down the nucleotide GTP. Contrary to this long-held view, we discovered that mutant RAS transitions between its active and inactive states—and demonstrated how the ability to cycle can be exploited therapeutically by inhibitors targeting either of its states. We identified cellular proteins and pharmacologic approaches that enable mutant RAS to hydrolyze GTP, thus restoring its natural GTPase function and leading to its physiologic inactivation in cancer cells. We co-led the first-in-human trial of an inhibitor targeting KRAS(G12C), the most common RAS mutation in lung cancer, work that culminated in the first FDA-approved therapy for patients with this form of lung cancer. We showed how tumors adapt to RAS inhibition, uncovered genetic mechanisms of resistance in patients, and identified combination therapies that can improve patient outcomes. Together, these findings have advanced our understanding of RAS-driven tumor biology and promise to benefit a broad population of patients who had limited treatment options in the past. Lito’s work has been recognized with the Trailblazer Prize for Clinician-Scientists by the Foundation for the National Institutes of Health and the Seldin-Smith Award for Pioneering Research by the American Society for Clinical Investigation.

As an Innovation Fund investigator, Piro Lito, M.D., Ph.D., is teaming up with Carlos Carmona-Fontaine, Ph.D., to study the role that cell cooperation plays in the resistance to cancer therapy. The team recently discovered a noncell autonomous form of drug resistance in which tumor clones that become resistant to the sotorasib—a mutant KRAS inhibitor—protect neighboring sotorasib-sensitive cells from this treatment. By combining Carmona-Fontaine’s specialty in studying cancer cell cooperation with Lito’s expertise in the biochemical mechanisms of KRAS in cancer, the team will decipher how sotorasib-resistant tumor cells shield sensitive cells and whether this mechanism is present in other therapeutic interventions. The investigators will use quantitative live microscopy methods to examine how concurrent clones with different KRAS statuses respond to KRAS inhibitors and how they mutually influence each other during therapy. This work can reveal key aspects of cooperative resistance to sotorasib, its implications for tumor evolution, and how to refine therapies that target mutant KRAS in cancer.