Powering Breakthroughs in Targeted Cancer Therapies

From Static Snapshots to Dynamic Discovery 

For nearly a century, an imaging method called X-ray crystallography has been the cornerstone of the field of structural biology — the science of using 3D imaging to understand the structure and function of biological molecules. X-ray crystallography allows scientists to see life at the atomic scale, a resolution that Christopher Lima, PhD, likens to a “telescope that would allow you to see the date on a dime on the surface of the moon.” Dr. Lima, Chair of the Structural Biology Program at the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK) and Investigator at the Howard Hughes Medical Institute, leads a team of scientists who have used this method and newer ones, like cryo-electron microscopy (cryo-EM), to see “every atom in a molecule.” Their work has revealed the extraordinarily complex structures of proteins and other cellular components and helped usher in an age of structure-based drug and vaccine design.  

But even the most advanced structural imaging is static, which puts it at odds with its subjects. “Life is dynamic,” Dr. Lima says, “and we don’t want still pictures — we want movies.” Capturing molecules and cells in action can spotlight “what’s working and what’s not working,” he notes, and help bridge the knowledge gap between what something looks like and how it functions. 

The advent of AI and leading-edge computational methods are allowing Dr. Lima and his collaborators to make the monumental transition from static observation to active discovery. With these tools, researchers can visualize and localize cellular processes such as gene regulation, and even trace the molecular events that lead to disease from their earliest stages. Such technologies also facilitate high-resolution simulations that can predict interactions between proteins and small molecule drugs. These capabilities played a key role in conquering a challenge that has vexed cancer researchers and drug developers for more than 50 years. 

Cracking the KRAS Code 

KRAS is one of the most commonly mutated genes in cancer. More than 80% of pancreatic cancers, 45% of colorectal cancers, and 25% of non-small cell lung cancers are driven by changes in the KRAS gene that trigger uncontrolled cell growth, like a molecular switch stuck in the “on” position. Attempts to flip it with drugs had long failed, leading doctors to deem KRAS “undruggable.” They blamed the difficulty on the protein’s unusually smooth structure. “We thought it was like a tennis ball, with no grooves or pockets for drugs to bind to,” says Piro Lito, MD, PhD, Director of Basic and Translational Research in the Division of Solid Tumor Oncology, Member of the Human Oncology and Pathogenesis Program, and Enid A. Haupt Chair of Therapeutic Research. Advances in structural biology helped prove this assumption wrong and informed the development of the first KRAS inhibitors, which teams at MSK helped lead to FDA approval in 2021 and 2022. 

The initial breakthrough came in 2013, when researchers at the University of California, San Francisco, reported a novel — and successful — approach to inhibiting a single amino acid found only in mutated KRAS proteins. The drug’s interaction with the protein, first visualized using X-ray crystallography, uncovered a never-before-seen drug-binding pocket that made it possible to turn the gene off. That finding sparked renewed enthusiasm for targeting KRAS and ushered in a new era of treatment for some of the most challenging and deadly cancers. 

The Next Wave 

Dr. Lito, who has devoted the past 23 years to studying KRAS, built on the revelation of the protein’s binding site, and soon he and his collaborators were testing KRAS inhibitors in the lab at MSK. His team’s research explained how the early drugs worked and contributed vital insights to the development of the two KRAS inhibitors that were later approved by the FDA. The team is now advancing the next wave of KRAS-targeted drugs. This future-looking work is important for several reasons. First, existing KRAS inhibitors are only effective against a single KRAS mutation, called G12C. It is the most common KRAS mutation in non-small cell lung cancer, but colorectal and pancreatic cancers are typically associated with a different mutation, G12D. Additionally, patients treated with G12C inhibitors often become resistant to the drug as their tumors evolve new mutations. To solve this problem, Dr. Lito’s lab is working to find drugs that can disable the gene’s defective molecular switch in new ways. In a separate effort, he is developing therapies that simultaneously target a wide range of KRAS mutations. These drugs are now in clinical trials. 

Looking Ahead 

Research that began with an undruggable target has become an area of explosive discovery at MSK thanks to the ingenuity of our doctors and scientists and the ongoing support of our donor community, whose generosity makes advancements in structural biology and drug development possible.  

Yet even amid the exciting progress shared by Dr. Lima and Dr. Lito, there is much more to be done. Dr. Lito notes that response rates to experimental KRAS inhibitors vary widely, and in some trials just 30% of patients respond to these treatments. “Our goal for the next 5 or 10 years is to create better inhibitors and better therapeutics to get the response rate up to 80% or 90%,” he says.