From Undruggable to Unstoppable: The State of KRAS Drug Development in Pancreatic Cancer

WHAT KRAS MEANS AND WHY IT MATTERS

KRAS is what scientists call an oncogene – a gene that, when mutated, can promote uncontrolled cell growth and lead to cancer. In its normal state, KRAS acts like an on/off switch that controls when cells divide. But when mutated, it can get stuck in the “on” position, constantly telling cells to grow. 

KRAS mutations drive about 11% of all cancers, but pancreatic cancers are the most dependent on KRAS. More than 90% of pancreatic ductal adenocarcinomas (PDAC) have a KRAS mutation, making it one of the most important and promising targets in pancreatic cancer research today.  

WHAT’S AVAILABLE TODAY VS. WHAT’S IN TRIALS

few drugs that target a specific KRAS mutation called G12C (such as sotorasib and adagrasib) are already FDA-approved for some lung cancers, and adagrasib is also approved for  colorectal cancer. However, KRAS-G12C is rare in pancreatic cancer (only about 1–2% of PDAC tumors), so these drugs have not meaningfully changed pancreatic cancer care, and they are not yet approved for this use. Nonetheless, recent clinical trials have shown encouraging signs of activity in pancreatic patients with KRAS G12C mutations, providing hope for future targeted therapies. 

The big need in pancreatic cancer is for drugs that can inhibit the KRAS mutations most common in PDAC – especially KRAS-G12D, found in roughly 45% of cases – or even block multiple KRAS mutations at once. 

Right now there are more than 60 RAS drugs in development, though two main classes of drugs are leading the charge in pancreatic cancer: 

1. “RAS(ON”/multi-KRAS inhibitors

Daraxonrasib (RMC-6236; Revolution Medicines) is designed to bind to and inhibit “active RAS,” targeting several KRAS mutations common in pancreatic cancer. 

• Early results from Phase 1 studies have shown tumor shrinkage and disease control in many patients with previously treated PDAC. 
• A global Phase 3 trial is now under way to test whether it improves outcomes versus current treatments, including in both metastatic and post-surgery (adjuvant) settings. 
• These results have generated significant optimism and national attention, as early patient responses demonstrate that KRAS, long considered “undruggable,” may finally be vulnerable. 

2. Direct KRAS=G12D inhibitors

MRTX1133 (Mirati/Bristol Myers Squibb) is the first drug designed to directly block the KRAS-G12D mutation itself. 

• It’s currently in a Phase 1/2 trial (NCT05737706) for multiple solid tumors, including pancreatic cancer. 
• Lab studies showed strong anti-tumor activity in pancreatic models, and the trial is now testing safety, dosing, and early signs of efficacy in patients. 
• Other G12D inhibitors—such as zoldonrasib (Revolution Medicines)—are also entering the clinic, adding momentum and competition that may speed progress for patients. 

WHY COMBINATIONS MATTER

KRAS-driven tumors are adaptable. Resistance to KRAS-targeting drugs has already been observed in several cancer types. Researchers expect that combinations, pairing KRAS inhibitors with chemotherapy, immunotherapy, or drugs targeting related pathways (like SHP2, MEK, or ERK), will be key to achieving deeper, longer-lasting responses. Many such combination trials are under way across multiple KRAS-inhibitor classes. 

THE LUSTGARTEN + BREAK THROUGH CANCER IMPACT

The Lustgarten Foundation has committed $5 million to Break Through Cancer to accelerate the translation of KRAS science into patient benefit. This initiative, called Conquering KRAS in Pancreatic Cancer, brings together leading scientists from Dana-Farber, Johns Hopkins, MIT’s Koch Institute, MD Anderson, and Memorial Sloan Kettering. 

Together, the team is: 

• Collaborating with Revolution Medicines to understand why some patients respond to RAS(ON) inhibitors while others develop resistance—using tumor biopsies collected during treatment to study molecular changes in real time. 
• Designing smarter combination strategies to prevent or overcome resistance before it happens. 
• Sharing data and expertise across institutions, shortening the time from lab discovery to clinical trial. 

This level of collaboration is unprecedented in pancreatic cancer research and it’s exactly the kind of teamwork that Lustgarten and Break Through Cancer were built to enable. 

WHAT TO WATCH IN THE NEXT 12-18 MONTHS

1. Readouts from KRAS-G12D programs (e.g., MRTX1133) for early evidence of durable benefit in PDAC.
2. Phase 3 data from daraxonrasib (RMC-6236) – the first test of whether a RAS(ON) inhibitor can outperform today’s standard treatments for second line treatment.

3. Combination trial results pairing KRAS inhibitors with immune or pathway-targeted therapies.
4. Discoveries from the Break Through Cancer/Lustgarten collaboration that may help identify combination approaches or markers that can match the right patient to the right KRAS therapy sooner.
5. Movement of KRAS inhibitors into earlier-stage disease, including trials testing these drugs right after surgery or as part of first-line treatment.

WHAT THIS MEANS FOR PATIENTS AND FAMILIES

For the first time, drugs designed to target the most common KRAS mutations in pancreatic cancer are being tested in people, not just in the lab. Early results are promising, but confirmatory trials are essential before they become standard care. 

Because KRAS tumors can evolve, there likely won’t be a single treatment. Combination therapy, guided by biomarkers, will probably deliver the biggest gains. 

And thanks to collaborative science led by Lustgarten and Break Through Cancer, discoveries are being shared across institutions in real time, speeding progress toward a future with pancreatic cancer cures.  

HOW TO LEARN MORE ABOUT TRIALS

If you or a loved one has pancreatic cancer, ask your doctor whether KRAS testing has been done. Knowing your KRAS mutation can determine whether you qualify for one of the many KRAS-targeted clinical trials now enrolling – such as those studying daraxonrasib, MRTX1133, or newer candidates. 

Up-to-date listings can be found on ClinicalTrials.gov or at lustgarten.org/clinical-trials. 

BOTTOM LINE

KRAS, once considered untouchable, is now one of the most active frontiers in pancreatic cancer research. With Lustgarten driving coordinated, multi-center science, the field is entering a new era where KRAS-targeted combinations may finally offer more time and hope for patients and families.