RAS Inhibition: A New Era for Pancreatic Cancer Treatment
The RAS family of proteins have long been an area of study for understanding and targeting in pancreatic cancer. The exciting clinical validation of daraxonrasib, a RAS inhibitor, in metastatic pancreatic cancer presented during the 2026 ASCO Annual Meeting, heralds a new era of treatment. RAS inhibition now has the potential to transform the standard of care for patients allowing both longer survival and an increase in quality of life. A follow up to our Overview of KRAS, here we highlight the importance of RAS and KRAS proteins in pancreatic cancer, provide an update on the newest advances in targeting KRAS/RAS proteins, and share insight on how these results may be applied to patient therapy.
What are RAS proteins?
The RAS family of proteins are involved in multiple signaling pathways that regulate cell growth, replication, and survival. There are three slightly different versions (called isoforms) of RAS protein called KRAS, NRAS, and HRAS. These isoforms are expressed in different cell types at different times but take part in similar signaling pathways. KRAS is the most highly expressed RAS isoform but because isoforms are similar, they can substitute for one another.
What is the significance of KRAS to pancreatic cancer?
More than 90% of pancreatic ductal adenocarcinomas (PDACs), the most common type of pancreatic cancer, have mutations in the KRAS gene. Mutations in the KRAS gene are found in ~20% of all cancers (most commonly PDAC, non-small cell lung cancer, and colorectal cancer) and result in the over-active signaling of growth and survival pathways that allows cancer cells to thrive.
There are multiple common mutations that occur in the KRAS gene to activate KRAS protein signaling and the specific mutations can differ between cancer types. In pancreatic cancer, KRAS mutations are almost always the first mutation that initiates cancer development and the two most common mutations are G12D, found in ~40% of PDAC tumors, and G12V, found in 29% of PDAC tumors.
90%+
of PDAC tumors have KRAS mutations
~40%
of PDAC tumors carry the G12D mutation
29%
of PDAC tumors carry the G12V mutation
What is targeted therapy?
Targeted therapy blocks specific molecules or pathways that are mutated or dysregulated and drives cancer progression to selectively kill cancer cells while sparing healthy cells. Chemotherapy targets rapidly dividing cancer cells by interfering with processes associated with replication and often affects healthy cells that undergo rapid cell division causing adverse events or side effects.
Because KRAS mutations are so prevalent in PDAC, KRAS signaling has been a pathway of intense interest. Until recently the RAS family of proteins was thought to be “un-druggable” due to the inability of drugs to bind to them. In 2013 researchers discovered a location for drug binding on a specific mutant version of KRAS called KRAS G12C (Ostrem JM et al. 2013. Nature). This advancement renewed efforts to drug RAS and opened the floodgates for new KRAS and RAS inhibitors to be developed.
Types of KRAS/RAS targeted therapies*
Since the discovery of KRAS G12C inhibitors, the ability to target KRAS has broadened and there are currently three ways to target mutant KRAS or RAS proteins in cancer. These range from:
- drugs that inhibit specific KRAS mutants (such as KRAS G12C inhibitors)
- drugs that bind and inhibit all KRAS proteins (isoform selective or “pan KRAS” inhibitors)
- and drugs that bind all RAS proteins regardless of isoform (multi-selective or “pan RAS” inhibitors).
Mutation Specific Inhibitors
Mutant KRAS specific inhibitors bind to and inhibit specific mutant versions of KRAS protein and do not affect wildtype KRAS and other RAS isoforms. While KRAS G12C specific inhibitors were the first to be developed, that mutation is only found in 1% of PDAC tumors and ~85% of tumors have either G12D, G12V, or G12R mutations. While there have been numerous KRAS G12C inhibitors in clinical trials since 2019, there are less than 10 KRAS G12D targeted therapies and one KRAS G12V targeted inhibitor currently under early clinical evaluation.
Isoform selective or “Pan KRAS” Inhibitors
Isoform selective or “pan KRAS” inhibitors bind to and inhibit the KRAS isoform (with or without mutations) of the RAS protein but do not affect other isoforms such as NRAS or HRAS. Since at least 90% of PDAC tumors harbor a KRAS mutation, this type of drug could impact a majority of patients. There are around five pan KRAS inhibitors in early clinical trials.
Multi-Selective or “Pan RAS” inhibitors
Multi-selective or “pan RAS” inhibitors bind to wildtype and mutant RAS protein family members, including KRAS, NRAS, and HRAS. Currently there are two RAS inhibitors under clinical development; daraxonrasib, which has been clinically validated in pretreated, metastatic PDAC patients and soon to be submitted for FDA approval, and ERAS-0015 which is still in early phase clinical trials.
Acquired Resistance
Acquired resistance to any therapy is a concern but because signaling pathways in cancer cells can be rewired to survive more readily than healthy cells, the ability to evade targeted therapies in cancer is a real clinical concern. There are multiple ways cancer cells can develop resistance to KRAS/RAS targeted therapies and the different mechanisms for targeting KRAS or RAS protein currently in clinical trials have different potential for developing drug resistance.
What does the success of daraxonrasib mean for research and therapy going forward?
The clinical validation of daraxonrasib has the potential to change the standard of care for metastatic pancreatic cancer patients moving forward. Revolution Medicines has applied for and received FDA approval on an Extended Access Program and currently have additional late-stage clinical trials evaluating daraxonrasib in metastatic PDAC patients as a first line treatment. In the near future, it is likely that this drug will become the standard of care for metastatic PDAC patients. However, there will need to be more therapeutic options to combine with RAS/KRAS targeted therapy to provide durable responses to the most patients, both newly diagnosed and those needing a second or later line of treatment.
Recent Hirshberg Foundation Seed Grants have been awarded to researchers who anticipate this need and are actively working to provide information to help achieve a menu of therapies that will be able to treat PDAC patients alone or importantly, in combination with RAS/KRAS targeted therapies.
Evan R. Abt, PhD
Assistant Professor, UCLA Molecular and Medical Pharmacology · 2022 Hirshberg Seed Grant RecipientRecognized that an unintended consequence of KRAS targeted therapy in PDAC tumor cells was the production of adenosine which is immunosuppressive. His project centers on evaluating how adenosine is produced by KRAS inhibition and identifying combination therapies that could inhibit adenosine production and perhaps make tumor cells more sensitive to immunotherapy.
Conan Kinsey, MD, PhD
Assistant Professor, University of Utah Huntsman Cancer Institute · 2024 Hirshberg Foundation Seed Grant RecipientIs evaluating the use of KRAS targeted therapies for pancreatic cancer prevention. KRAS mutations can be found in precancerous lesions called Pancreatic Intraepithelial Neoplasia or PanINs which are thought to be the most common precursor to PDAC. Dr. Kinsey’s project focuses on determining whether treating PanINs with KRAS inhibitors can limit the development of PDAC in preclinical models.
Fredrik Ivar Thege, PhD
Assistant Professor, The Ohio State University Comprehensive Cancer Center · 2024 Hirshberg Foundation Seed Grant RecipientSet out to identify factors that drive resistance to KRAS targeted therapies such as daraxonrasib using CRISPR screening technology. Identified factors are being evaluated in combination with KRAS targeted therapy in Patient-Derived Organoids to generate treatment combinations to test in the clinic.
Richard Ebright, MD, PhD
Clinical Fellow, Dana-Farber Cancer Institute · 2025 Hirshberg Foundation Seed Grant RecipientHas identified the Fibroblast Growth Factor Receptor (FGFR) signaling pathway as a potential target for inhibition in combination with KRAS signaling for increased killing of pancreatic cancer cells and is currently screening clinically available inhibitors to evaluate the effect of dual inhibition in preclinical models.
Kirsten L. Bryant, PhD
Assistant Professor, University of North Carolina at Chapel Hill · 2025 Hirshberg Seed Grant RecipientSeeks to identify new therapeutic targets for PDAC by evaluating the metabolic signaling pathways in tumor cells undergoing RAS inhibition. Potential targets will then be evaluated in combination with RAS inhibition to increase treatment response and potentially development into clinical combinations.
The Hirshberg Foundation is proud to provide funding for basic science and early clinical hypotheses to forward the understanding and treatment of pancreatic cancer research.
We are dedicated to the identification and support of novel ideas to drive scientific breakthroughs for this difficult to treat disease.
References for more detailed information on RAS/KRAS targeted therapies