Diana Turner explores the latest KRAS breakthroughs and how our understanding of this illusive protein has developed in recent years. 

In September 2025, the inaugural Stephenson Global Prize was awarded to Dr Frank McCormick, Professor at the UCSF Helen Diller Family Comprehensive Cancer Center, for “groundbreaking discoveries that have transformed the fight against pancreatic cancer”. 

The Stephenson Global Prize, the flagship programme of the Stephenson Global Pancreatic Cancer Research Institute (SGPCRI), is designed to empower visionary researchers with the resources to accelerate discoveries that could change the trajectory of disease treatment. 

Dr McCormick was honoured for uncovering how mutations in the KRAS gene drive tumour growth. 

“This recognition is deeply meaningful,” says Dr McCormick. “Pancreatic cancer remains one of the most challenging diseases we face, and I’m honoured to share this award with my lab as we continue exploring new ways to target KRAS and develop therapies that could change lives.”

Uncovering the mysteries of KRAS

Changes to the KRAS gene, which is important in controlling cell growth, can lead to cells growing and dividing out of control to form tumours. Mutations in KRAS are found across 25% of cancers and are commonly found in several hard-to-treat cancers, featuring in 90% of pancreatic cancers, 50% colorectal cancers and 25% lung adenocarcinomas. 

Despite the prominent role of KRAS mutations in cancers being known for decades, scientists struggled to find ways to target this pathway. The protein was considered an impossible or undruggable target, as Dr McCormick explains, it has no available pocket to which a drug can bind and has been compared to a “squishy tennis ball”. 

Dr McCormick and his team uncovered how mutations in the KRAS gene drive tumour growth. He explains: “When cells are exposed to growth factors, RAS proteins are turned ON, initiating a signalling cascade that instructs cells to proliferate.  Within minutes, RAS proteins are turned OFF again. We discovered the proteins that turn RAS OFF, and named them GAPs, for GTPase Activating Proteins. We also discovered that oncogenic RAS proteins are completely resistant to GAPs and therefore cannot be turned OFF. Persistent signalling from these mutant proteins causes uncontrolled proliferation, leading to cancer.” 

This expanded understanding of KRAS proteins’ impact on cancer has led to the discovery of new targeted treatments for hard-to-treat cancers. Dr McCormick expands: “Lung adenocarcinomas and colorectal cancers with KRAS mutations have been excluded from treatment with targeted therapies in the past. Pancreatic cancer patients, most of whom have KRAS mutations, have never had the option of a targeted therapy. Now all these patients are likely to have opportunities to participate in clinical trials involving KRAS inhibitors, offering immediate hope of better outcomes in the short and long term.” 

The first approved drug to target a KRAS mutation was sotorasib (Lumakras), which was granted accelerated approval by the US Food and Drug Administration (FDA) in 2021 for non-small cell lung cancers. This was followed by dagrasib (Krazati), which was approved in December 2022. Both of these drugs only target the G12C variant, which accounts for about 11-13% of all KRAS mutations, though more than 30 other compounds targeting various KRAS mutations are currently in clinical evaluation (1).

KRAS inhibitors in clinical trials

In the most significant breakthrough in recent years, in 2025, avutometinib and defactinib were approved by the FDA for KRAS-mutated low-grade serous ovarian cancer (LGSOC), representing the first registration of a FAK inhibitor drug and the first registration of a dual RAF-MEK clamp. 

Other drugs in clinical development target specific forms of common KRAS oncogenes, like KRAS G12D, G12R and KRAS G12V. 

A novel cancer vaccine (ELI-002 2P) developed at the UCLA Health Jonsson Comprehensive Cancer Center has been shown in Phase I trials to trigger powerful and lasting immune responses in pancreatic and colorectal cancers driven by G12D or G12R KRAS mutations (2). 

After an extended follow-up of 19.7 months, the researchers found that median relapse-free survival was 16.33 months and median overall survival was 28.94 months with the greatest benefit seen in patients who developed strong mKRAS-specific T cell responses. A total of 84% of patients (21 out of 25) generated KRAS-specific T cells, including both CD4+ helper cells and CD8+ killer cells. Importantly, many of these T cells persisted over time. In 24% of patients (three pancreatic, three colorectal), the biomarkers associated with the tumour were completely cleared. Interestingly, 67% of tested patients developed immune responses to additional tumour-associated mutations, suggesting potential for broader anti-tumour activity.  

“Targeting KRAS has long been considered one of the difficult challenges in cancer therapy,” says first author of the study Zev Wainberg, Professor of Medicine at the David Geffen School of Medicine at UCLA and researcher in the UCLA Health Jonsson Comprehensive Cancer Center. “This study shows that the ELI-002 2P vaccine can safely and effectively train the immune system to recognise and fight cancer-driving mutations. It offers a promising approach to generating precise and durable immune responses without the complexity or cost of fully personalised vaccines.” 

The research team has completed enrolment in a larger Phase II study of ELI-002 7P, a next-generation version of the vaccine that targets a broader set of KRAS mutations. 

Another significant Phase I study has emphasised the value of combination treatments for targeting KRAS mutations. Findings from Cardiff Oncology’s Phase Ib portion of the Phase Ib/II study in patients with KRAS-mutated metastatic colorectal cancer (mCRC) underscored the safety profile of onvansertib when combined with the standard-of-care (SoC) chemotherapy+bevacizumab (3). The results show that the combination has a lasting response, indicating its tolerability and efficacy in treating mCRC patients whose tumours harbour various KRAS mutations. The FOLFIRI+bevacizumab+onvansertib combination demonstrated efficacy across multiple KRAS mutations, supporting the team’s follow-up CRDF-004 first-line study in RAS-mutated mCRC.

Overcoming the challenges of KRAS targeting

Meanwhile, preclinical studies have revealed new findings related to KRAS mutations. In 2022, a team at University of California, San Francisco (UCSF) demonstrated that KRAS drugs could be used as permanent flags for cancer cells. They also designed an antibody that recognised the unique drug/KRAS surface fragment and beckoned to immune cells. Building on this work, Kliment Verba, Assistant Professor of Cellular and Molecular Pharmacology at UCSF, is using cryo-electron microscopy to visualise the ‘radiation sandwich’ in atomic detail, giving the field a structure to develop even better antibodies. “The drug bound to the KRAS peptide sticks out like a sore thumb, which the antibody then grabs,” explains Verba. “We’ve taken a significant step toward patient-specific radiation therapies, which could lead to a new paradigm for treatment.” 

Researchers at the Francis Crick Institute and Revolution Medicines have shown that combining a newly identified KRAS G12C inhibitor with a compound that blocks a protein called SHP and an immune checkpoint inhibitor in mice with lung cancer allows immunotherapies to target non-responsive tumours (4). In mice with functional immune systems, the triplet combination shrank the tumours and, in some mice, fully eradicated them. These mice were also more resistant to the lung cancer coming back after treatment. Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick, says: “Blocking genes like KRAS in lung cancer has led to some exciting new developments, but we still see problems with resistance. We’ve now been able to report partial or complete eradication of tumours in mice by combining KRAS and SHP2 inhibitors with immunotherapy.” 

Overcoming drug resistance is a persistent problem with therapies that target KRAS. Further research at the Francis Crick Institute, in collaboration with Amsterdam University Medical Centre, found that adding drugs that block regulatory T cells (Tregs) to combination treatments could help to reduce resistance to KRAS inhibitors (5). The study revealed that clusters of T cells were gathered near the tumours, as well as dendritic cells. When mice were given a KRAS inhibitor drug, these cell communities grew in size and were able to enter the tumour, but the Tregs were stopping immune cell coordination. When the researchers blocked the action of Tregs, the mice responded better to the KRAS inhibitor, showing reduced tumour growth and longer survival. 

It will be findings like these that eventually result in more effective KRAS inhibitors reaching patients.  

So what could be possible in the next five to ten years? Dr McCormick shares his aspirations for the field: “My hope is that the next generation of targeted KRAS inhibitors will be safe enough to use as preventative agents, to stop development of KRAS cancers altogether.”  

References

1. Kos T, Saur D. Breaking down KRAS: small-molecule degraders for cancer therapy. Sig Transduct Target Ther 2025:10:86.

2. Wainberg ZA, Weekes CD, Furqan M, et al. Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results. Nat Med 2025;31:3648–3653.

3. Ahn DH, Barzi A, Ridinger M, et al. Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study. Clin Cancer Res. 2024;30(10):2039-2047.

4. Anastasiou P, Moore C, Rana S, et al. Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade. Nat Commun. 2024;15(1):8146.

5. Cole M, Anastasiou P, Lee C, et al. Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses. Sci. Adv.2024;10: eadl6464. 

 From DDW Volume 27 – Issue 2, Spring 2026 – Read the digital issue here