RAS Initiative
The National Cancer Institute RAS Initiative endeavors to better understand the RAS oncogene and discover its vulnerabilities to treat RAS-related cancers.
About one-third of all human cancers are driven by mutations of the RAS family of genes.
Though scientists have known about RAS for more than 30 years, a treatment to block the oncogene has been elusive.
Our scientists investigate approaches to RAS-driven cancer from multiple angles and multiple fields. From protein production to assay development to structural discoveries, we contribute to the search for an effective RAS inhibitor.
Creating community to progress the field
When the National Cancer Institute RAS Initiative was founded in 2013, researchers studying mutated RAS proteins were decentralized, scattered across government and academic laboratories. Most major pharmaceutical companies had suspended or avoided drug development for RAS-related cancers because of the cost and poor chance of success.
Due to scientific limitations at the time, there was no obvious path to better understand the mutant proteins’ behavior in human cells or to discover treatments for the thousands of RAS-related cancers. But the fledgling project headquartered at the Frederick National Laboratory soon began to turn heads.
Through an open, collaborative model and under the guidance of the National Cancer Institute, we developed a united, international RAS research community.
The RAS Initiative’s aspirational goals and early progress, along with headway made by other groups, helped to reignite interest and inspire laboratories and industry to renew the search for treatments. Funded by the National Cancer Institute, the initiative continues to pursue progress in basic research and drug discovery for RAS-related cancers.
Ethan Dmitrovsky, M.D., Director, Frederick National Laboratory
Chris Kane, Ph.D., Program Officer for National Missions, Contracting Officer Representative, National Cancer Institute
Frank McCormick, Ph.D., RAS National Program Advisor, University of California San Francisco
Contact us at SolveRAS@nih.gov.
Goals
The overarching goal of the NCI RAS Initiative is to mobilize the cancer research community to develop ways to understand and target cancers driven by mutant RAS in an open model of collaboration among government, academic, and industry researchers.
The RAS Initiative was launched in 2013 to continue to spur innovation in the field through drug discovery and detailed studies on the structure, biochemistry, and biophysics of RAS.
The overarching model of the RAS Initiative is to nucleate more energy and focus on RAS biology and drug discovery through state-of-the-art science, and by providing resources, de-risking some of that effort by providing structures, assays, and reagents, and by coalescing the community.
An open model that advances RAS research
The RAS Initiative has adopted the “hub and spoke” model to mobilize the RAS research community.
Based out of the Frederick National Laboratory, the RAS Initiative acts as the hub that connects the larger community of RAS researchers located around the world, combining efforts and creating new ways to approach the complex issue of RAS.
This open model allows government, academic, and industry researchers around the world to collaborate and more effectively advance the field of RAS research.
Addressing the problem with RAS genes
It has been known for more than three decades that about a third of all human cancers, including a high percentage of pancreatic, lung, and colorectal cancers, are driven by mutations in RAS genes.
The main members of the RAS gene family— KRAS, HRAS, and NRAS—encode proteins that have a pivotal role in cell signaling. When RAS genes are mutated, cells grow uncontrollably and evade death signals.
RAS mutations also make cells resistant to most available cancer therapies. NCI launched the RAS Initiative due to the magnitude of this challenge, as well as the potential clinical benefit.
RAS Proteins and Their Regulators in Human Disease provides a recent review of the RAS problem. For a community view of the genes that comprise the larger RAS pathway, see our blog post, RAS Pathway v2.0.
Mutated RAS Proteins: Long Considered Undruggable
Mutant RAS proteins have been difficult to target, in part, because they are defective in an intrinsic enzyme activity, freezing them in the “on” (GTP-bound) state.
Despite repeated attempts, researchers failed to develop a drug that could inhibit the activity of RAS proteins in cancers. They had hoped to find a small molecule that could preferentially bind the unique features of the RAS protein, but they couldn’t find a surface on the protein that would bind a drug.
Many researchers in the drug discovery field became convinced that the RAS protein was undruggable.
But advances in technology and improved understanding of RAS signaling and regulation have created opportunities to address this situation.
Binding RAS: Hope from groundbreaking research
After years with little success, researchers developed groundbreaking techniques that rapidly advanced the field of RAS research.
In the 2010s, the Shokat Lab at the University of California San Francisco and the Fesik Lab at Vanderbilt University developed innovative drug screening and medicinal chemistry techniques that identified molecules that could bind mutated KRAS proteins.
In May 2021, the Federal Drug Administration approved a treatment for non-small-cell lung cancer (NSCLC), which targets the KRAS G12C mutation, giving new hope to NSCLC patients.
Drugging the once-undruggable: Research continues
The RAS research community has much to discover, and now it continues its work with renewed optimism.
After developing an approved treatment for NSCLC, many researchers seek to apply what they’ve learned to other tumors.
For example, mutated RAS proteins are present in 90% of pancreatic tumors, a cancer for which there are not yet any effective treatments.
Key accomplishments
Accomplishments of the RAS Initiative include key structural, biochemical, biophysical, technological advances and drug discovery.
- 3 RAS compounds co-discovered by the RAS Initiative along with BridgeBio Oncology Therapeutics and Lawrence Livermore National Laboratory are in clinical trials.
- The RAS Initiative was the first research team to produce, purify, and generate a crystal structure of fully processed KRAS4b. This advancement enabled biophysical analyses of KRAS in synthetic membranes and showed how processing is critical in complexes interacting with chaperone proteins.
- The RAS Initiative solved additional crystal structures of oncogenic KRAS proteins in complex with GTPase-activating proteins (GAPs).
- The RAS Initiative Research Team developed a range of cell-based, imaging, and biochemical screens to examine RAS activity, which have facilitated academic and industry collaborations.
- The RAS Initiative formed a, strategic, high-performance computing alliance with the U.S. Department of Energy (DOE) National Laboratories to bring new insight into RAS membrane dynamics.
Latest publications
Biophysical
and structural analysis of KRAS switch-II pocket inhibitors reveals
allele-specific binding constraints
Alexander P, Chan AH, Rabara D, Swain M, Larsen EK, Dyba M, Chertov O, Ashraf M, Champagne A, Lin K, Maciag A, Gillette WK, Nissley DV, McCormick F, Simanshu DK, Stephen AG
Published: 06/01/2025
BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction
Simanshu DK, Xu R, Stice JP, Czyzyk DJ, Feng S, Denson JP, Riegler E, Yang Y, Zhang C, Donovan S, Smith BP, Abreu-Blanco M, Chen M, Feng C, Fu L, Rabara D, Young LC, Dyba M, Yan W, Lin K, Ghorbanpoorvalukolaie S, Larsen EK, Malik W, Champagne A, Parker K, Ju JH, Jeknic S, Esposito D, Turner DM, Lightstone FC, Wang B, Wehn PM, Wang K, Stephen AG, Maciag AE, Hata AN, Sinkevicius KW, Nissley DV, Wallace EM, McCormick F, Beltran PJ
Published: 06/01/2025
NMR 1H,
13C, and 15N resonance assignments of the oncogenic Q61R variant
of human NRAS in the active, GTP-bound conformation
Sharma AK, Tonelli M, Dyba M, Gillette WK, Esposito D, Nissley DV, McCormick F, Maciag AE
Published: 05/01/2025
RAS Lab discussion forum
Research teams
Biochemistry & Biophysics Research Team
The team uses a variety of biochemical and biophysical assays to characterize the interaction between RAS proteins and their effectors in solution or on the membrane. Our researchers also develop assays to identity small molecules inhibitors of RAS.
Bioinformatics Research Team
The team provides data processing and analytical support and creates software tools to organize and interpret data produced by the RAS Initiative.
Chemistry Research Team
The team uses fragment-based drug discovery approaches to develop low molecular weight screening hits, known as fragments, into potent inhibitors with favorable drug-like properties.
Computational Chemistry Research Team
The team uses computers to aid in drug discovery. Our main tool is the software package UCSF DOCK, which we use for performing large-scale screens of hundreds of millions—soon to be billions—of molecules.
Drug Screening and Preclinical Research Team
The team strives to discover and develop compounds that directly target oncogenic RAS proteins.
Imaging Research Team
The team develops and applies new optical microscopy techniques to understand how RAS molecules move, interact, and signal in living cells.
Mass Spectrometry Research Team
The team employs cutting-edge protein analysis methods to better understand and target canonical RAS isoforms, RAS-related proteins, and RAS-dependent signaling pathways.
Reagents Research Team
The team supplies nucleic acids, cell lines, and protein reagents for the RAS Initiative. We support the development of structural studies, drug screens, imaging experiments, and cell biology and biochemistry projects.
Structural Biology Research Team
The team leads efforts on the structural characterization of RAS complexes to provide new structural and mechanistic insights into RAS biology and to identify new targets for structure-based drug discovery efforts.
Collaborations
The RAS Initiative has galvanized cooperative efforts across industry, government, academic, and other research institutions, leading to a deeper understanding of RAS biology and accelerating the pace of drug discovery.
The RAS Initiative uses strategic agreements, CRADAs, mCRADAs, and other partnership mechanisms to leverage collaboration across fields and institutions.
RAS Lab discussion forum
RAS Lab is an online discussion forum on Basecamp the RAS Initiative launched to further its goal to increase the exchange of scientific information and collaboration on RAS research.
If you would like to join RAS Lab, send an email to SolveRAS@nih.gov with the subject line "I would like to join RAS Lab."
Policies
- RAS Lab promotes open and informal scientific discussion. Posts that are derogatory, offensive, political, or commercial in character are not appropriate and will be removed.
- The NCI does not acquire or maintain any personal identification information from RAS Lab.
- For more information, see the section on third-party sites under NCI's Privacy and Security Policy, or view Basecamp's security policy and privacy policy.
RAS Initiative Symposium
The RAS Initiative hosts a symposium every other year to bring together multidisciplinary RAS and cancer researchers from across the globe.
This three-day international symposium includes featured invited presentations, short presentations from selected abstracts, and poster presentations. This event is held in person in Frederick, Maryland with virtual components.
