Cracking the KRAS Code

Once considered undruggable, KRAS research has exploded, with scientists developing and testing drugs that target specific variants of the oncogene.

Until recently there were no KRAS inhibitors available to patients outside of a clinical trial. That changed in May 2026, when the FDA authorized expanded access for daraxonrasib (RMC-6236), Revolution Medicines’ investigational pan-RAS inhibitor. This program provides patients with previously-treated metastatic pancreatic cancer access to the promising, orally-administered drug while regulatory reviews continue. For Despina Siolas, M.D., Ph.D., a physician–scientist who treats pancreatic cancer, the news signaled a potential game changer for patients. “Pancreatic cancer is such a complex disease, and it’s never going to be a one-size-fits-all approach,” she says. “But KRAS inhibition could prove to be a such a huge win for patients. But it’s important to note this is just the beginning. We have so much more to learn.”

Siolas is a medical oncologist at Weill Cornell Medicine and Assistant Professor of Medicine at Weill Cornell Medical College (New York City). She leads her own lab focused on gastrointestinal cancer research, where she is trying to unravel the hidden vulnerabilities of KRAS, the most common genetic mutation in pancreatic cancer.

The Year of KRAS

Indeed, with more KRAS inhibitors in the pipeline, it’s essential to discover more about the biology of the oncogene so “quick pivots” can be made in trying new approaches in clinical trials that may prove more beneficial, Siolas adds.

“This is the year of KRAS inhibitors,” she continues. “There are going to be considerable efforts I believe in trying different combinations, maybe a combination with immunotherapy or with another inhibitor. Maybe we need to look at giving an inhibitor prior to surgery or post-surgery. There are many scenarios. But all of this is great news for our patients.”

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Much of the research conducted in her lab focuses on observing clinical data and then taking that data back to the lab to develop investigations. Once the investigation is complete, the information from the experiment goes back to the clinical setting. Among the investigations is a focus on how pancreatic malignancies create a hostile environment that is densely fibrous and suppresses the immune system. The end result: Chemotherapy and immunotherapy can’t reach cancer cells, making standard treatment often futile.

“We are working really hard to try to figure out how different RAS mutations affect a patient’s response [to medication] and [clinicians’] treatment decisions,” Siolas explains. “But at the same time, we are also looking at how the mutations affect the cell’s biology.”

Pivotal Studies

A multicenter study that Siolas and her colleagues at Weill Cornell were involved in showed a common mutation found in the KRAS gene appears to have weak biological activity leading to less distant invasion in pancreatic cancer. The research, published in September 2024 in the journal Cancer Cell, shows that KRAS mutations, such as the most common KRAS G12R, KRAS G12D, and KRAS G12V, could potentially provide physicians with important information about prognosis as well as more personalized, appropriate treatment.

To better understand early- and late-stage pancreatic cancer, both in terms of outcomes and biology, the team used data from 1,360 patients. With sophisticated methods of genetic testing, the team found that KRAS G12D, the most common mutation, occurring in 35 percent of study patients, was associated with aggressive cancer and the worst outcomes. The variant was also linked with increased rates of distant recurrence, or metastatic disease, arising after an operation to remove a tumor.

KRAS G12V, which occurred in about 30 percent of patients, was associated with better overall survival, as was KRAS G12R, which was present in 15 percent of patients. However, KRAS G12R was also associated with increased rates of recurrence in and around where a pancreas resection was performed.

The research team suggested a revision to clinical guidelines that would recommend molecular testing in all patients with pancreatic cancer. Current guidelines only recommend molecular testing for patients with later-stage, locally advanced or metastatic pancreatic cancer, but not for early-stage patients.

“We have all of this information now and the work is ongoing so we expect to publish more data soon,” Siolas explains.

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Find a trial

She and her team are also partnering with Tezcat Biosciences to develop new treatments for pancreatic cancer. Supported by a National Cancer Institute grant, this collaboration aims to utilize receptor-independent drug delivery technology to target aggressive cancers. A major focus will be attempting to bolster pancreatic cancer research by leveraging Tezcat’s drug delivery technology. Plus, Project Purple has just recently invested $375,000 to support pancreatic cancer research at Weill Cornell Medicine. This two-year Research Recovery Grant is designed to shore up and sustain important research following recent funding gaps. 

Siolas is hopeful about the future in pancreatic cancer research and treatment. “There has been a significant change in the last 10 years for the better, but people want a cure and that hasn’t happened,” she says. “But for some patients the advances made have led to longer survival. We are headed in the right direction, and there are a lot of smart people working to improve outcomes for our patients.”

She recalls an important piece of advice given to her by the late Greg Hannon, Ph.D., one of her mentors. “Basically, he said research breakthroughs happen because a thousand people are chipping away at a problem, rather than one person yelling ‘Eureka,’” she adds.