It’s not often that slide presentations at medical conferences prompt thousands of audience members to leap to their feet, some embracing or openly weeping.

But that’s what happened when pancreatic cancer specialist Brian Wolpin, MD, MPH, began to present his latest research at the American Society of Clinical Oncology meeting in Chicago this past May.

A hush fell over the crowd. Wolpin began to report “a statistically significant improvement in overall survival…” Before he could finish his sentence, the audience erupted.

It was a milestone many in the room had only dreamed possible: Patients with metastatic pancreatic cancer who took a daily pill called daraxonrasib lived nearly twice as long as those treated with chemotherapy.

“I’m getting chills telling you about it,” said Kimryn Rathmell, MD, PhD, a kidney cancer specialist who was in the audience that day. “It was a celebration for all of us that one of the major battles has been won.”

The phase 3 findings were particularly important to those living or working in the world of pancreatic cancer, a particularly cruel and hard-to-treat malignancy. Because mutations in KRAS, a member of the RAS family of genes, occur in more than 90% of pancreatic cancers, nearly a third of lung adenocarcinomas, and roughly 40% of colorectal cancers, a wide array of curious specialists, such as Rathmell, also filed into the auditorium.

As director of The Ohio State University Comprehensive Cancer Center and former director of the National Cancer Institute (NCI), Rathmell views the tale of RAS as a sort of hero’s journey — a telling example of how public funding for uncertain and often unglamourous basic science can ultimately lead to life-changing discoveries.

Federal agencies, such as the National Institutes of Health and NCI, are often the main funding source for the initial legwork, the basic science in rodents and petri dishes required to understand the biology and structure of a target. These experiments can take decades before any tangible therapeutic molecules emerge. Commercial biotech and pharmaceutical companies can then leverage this potential into new drugs that ultimately move from the bench to the bedside.

“If any one of those pieces were lost in the funding ecosystem, we would not be where we are today,” Wolpin said.

The ‘Mount Everest’ of Cancer Research

Looking back on that moment at the podium, Wolpin says he couldn’t help but get emotional as he stood there thinking about his patients.

“I’ve taken care of a lot of people with pancreatic cancer over the past 20 years and the vast majority of them are not alive,” he said. “It’s a hard disease.”

Pancreatic cancer doesn’t have a lot of warning signs, so people are often diagnosed late. The organ rests deep in the abdomen, so tumors are hard to spot with scans. The cancer metastasizes early and has historically responded poorly to chemotherapy and immunotherapy. The disease is also painful and extremely fatiguing.

Early in his career, Wolpin was stunned to find that many of his patients died within 3 months of diagnosis. Even today, pancreatic cancer has an overall 5-year relative survival rate of just 13%.

“Unfortunately, a lot of the advances we have made in other cancer types haven’t worked for pancreatic cancer,” he said.

The failures largely rest on the back of KRAS. The most frequently mutated oncogene in human cancers, it has proven a formidable foe, with decades of unsuccessful efforts to drug RAS, companies abandoning programs in the aftermath, funders balking, and some scientists giving up.

The story is a long one — filled with false starts, failures, and frustrations — before efforts to drug KRAS in pancreatic cancer began to show real promise.

A pivotal moment on this journey began in the lab in the early 1980s.

Geneticist Channing Der, PhD, had just started his postdoctoral training in Geoffrey Cooper’s lab at Harvard Medical School when he started sprinkling purified DNA from human cancer cells onto mouse cells.

The question he and other scientists around the country were racing to answer at the time: What genes could transform a normal cell into a cancer cell?

After more than a dozen experiments, Der had struck out. The project, he recalled, seemed doomed to fail, until his final experiments ultimately produced an answer: RAS genes.

“This marked the very first identification of human cancer genes,” said Der, now a professor of pharmacology at University of North Carolina at Chapel Hill. “Little did I know at the time that this discovery would help lead to the moment we have now.”

At least two other labs had made similar landmark discoveries at almost the same time.

The genes they found were members of the RAS family, whose cancer-driving versions had first been identified in retroviruses in rats in the 1960s (thus the name, which stands for rat sarcoma). Through hundreds of small, iterative studies in labs around the country, we have since learned that the RAS proteins these genes make are essentially molecular switches, relaying signals from the cell surface which instruct the cell to divide or be still.

Cancer-associated mutations disrupt this process, leaving the switch stuck in the on position so cells proliferate uncontrollably, leading to tumors.

Three RAS siblings — KRAS, HRAS, and NRAS — have been the focus of most research.

The discovery opened a new field of cancer research, but it also revealed an exasperating challenge.

“It is a terrible feeling to know the reason why a cancer develops and not be able to do something about it,” said chemist Kevan Shokat, PhD, a professor in the Department of Cellular and Molecular Pharmacology at the University of California San Francisco and academic co-founder of Revolution Medicines, which developed daraxonrasib. “It’s like Mount Everest. It’s sitting there. Everybody knows that you have to climb it, but due to the protein’s structure and the RAS pathway being so complicated, it basically couldn’t be achieved.”

Drugging the ‘Undruggable’

Scientists often describe KRAS as a greasy or squishy ball which, unlike other proteins targeted for cancer therapy, doesn’t have any obvious pockets for a drug to latch on to and block its function.

Other efforts to block KRAS by inhibiting associated enzymes looked promising in the lab but failed in the clinic, disappointing patients and turning off investors and scientists.

“People thought, whatever we do to this protein, the tumor is going to figure it out anyway,” recalled Shokat. “It didn’t look like it would be druggable.”

In 2013, Shokat and his colleagues discovered a tiny, hidden pocket in a common cancer-fueling mutation of KRAS, called G12C, and showed a molecule could latch onto it.

Shokat was, appropriately, about to drive up a snowy mountain road in Lake Tahoe, California, with his family for the weekend when he got a message from his postdoctoral researcher, Ulf Peters.

“He said, ‘Look inside this file, and you’ll see the structure. I think you will like it,’” Shokat recalled.

Shokat had to wait hours until he arrived at his destination to open that file. When he did, he had his family gather round.

“I looked at it and said, ‘Holy crap!’” he recalled. The image revealed a molecule that fit neatly in the small, buried pocket on the protein.

That molecule did not ultimately become a successful drug. But Shokat’s research had confirmed it was possible to drug KRAS. The protein no longer seemed untouchable.

About that time, Harold Varmus, MD, a Nobel Prize-winning cancer researcher, launched the RAS Initiative, which directed substantial resources toward RAS research.

“Diverging millions of dollars per year to one initiative was definitely controversial, but it was what was needed to get this to a place where it could move into the commercial sector to get it into the hands of patients,” said Rathmell, who served as the NCI director from 2023 to 2025.

Companies across the country also began testing compounds to target KRAS and its less-common siblings in slightly different ways.

The term ‘undruggable’ had morphed from a deterrent to a motivation, Shokat said.

The race to the mountaintop was on.

Early Victories

In 2021 and 2022, the FDA approved two KRAS inhibitors — first sotorasib and then adagrasib — to treat locally advanced or metastatic non-small cell lung cancer by binding to the KRAS G12C-mutant protein.

But the G12C mutation is rare in pancreatic cancer, prompting investigators to look for other ways to target RAS in this population.

Daraxonrasib does just that. The drug works more like a piece of two-sided sticky tape which enters the cell, sticking to a separate chaperone protein called cyclophilin A and then to RAS. This ignites a complex chemical reaction that, essentially, can turn the stuck switch from on to off.

Fast forward to 2022, and Wolpin approached phase 1 clinical trials of the drug in pancreatic cancer with caution.

“We always go in holding back too much excitement until we really see what’s going to happen with patients,” he said.

But within the first few weeks, some patients reported that their pain had gone away.

“That was the first sign to me that this was going to work” he recalled.

That same year, Paul Cress, a father of two and grandfather of five from Delaware, Ohio, went to his doctor feeling tired and anemic. Days later he got a call back.

“It’s probably one of the worst things you could ever hear in your life,” said Cress, who was diagnosed that year with stage II pancreatic cancer. “I’m not sure I even heard the rest of the conversation.”

Since then, Cress’s cancer has metastasized. He has had multiple surgeries and spent many days at The Ohio State University outpatient cancer center having chemotherapy to knock down the tiny tumors that kept popping up.

He feels lucky to be alive.

But when he started following the story of RAS, and heard about Wolpin’s talk, he felt another emotion: hope.

In August 2026, just 3 months after Wolpin’s presentation, the FDA approved daraxonrasib for adults with metastatic pancreatic adenocarcinoma who, like Cress, had progressed on previous therapies.

“This is the biggest game changer that has come along in any type of research since the Salk vaccine for polio,” said Cress, now 77.

A Promising but Uncertain Future

Wolpin stresses that daraxonrasib is not a cure.

The 500 patients enrolled in the phase 3 trial already had metastatic cancer and at least one previous chemotherapy treatment.

Those assigned to take the drug vs chemotherapy lived a median of 13.2 vs 6.7 months. Their cancer remained under control for longer, and their quality of life improved.

The side effects were real, including an often severe rash and mouth sores. But treatment-related adverse events only led to discontinuation in about 1% vs 11% of patients taking the drug vs chemotherapy.

The big questions now facing researchers: How can such side effects be reduced? How can recurrence and resistance be prevented and survival improved? And how can the lessons from RAS be harnessed to address other cancers?

Still, the approval of a drug like daraxonrasib that targets multiple forms of RAS marks a new and important milestone. Knowing it can be done is now motivating others to try to do it better.

By one account, at least 79 RAS-targeting drugs are now being tested in 238 clinical trials worldwide.

“There are already other drugs that have been reported by academics to be better than daraxonrasib in mouse studies and in the test tube,” said Shokat. “As these get better, the clinical benefit will ultimately get better too.”

Some worry that in the face of increased politicization of science, funding cuts, and proposed changes to the way federal funding is distributed, the cell and animal studies required to answer these essential questions may be stalled.

“The current funding situation is frightening and demoralizing,” said Der “I’ve had people in my own group quit because they have not been able to get funding.”

He and others who have spent their lives working on RAS are hopeful that its story could drive home the importance of such funding.

Cress, who took his first daraxonrasib pill on September 10, is also hopeful.

“If this pill wasn’t available, I probably would have stayed on chemo for a few more years and then decided that ‘enough is enough’ and just let life take its course,” he said. “With this, I tell you, I see a light at the end of the tunnel.”

The experts cited in this article had no relevant disclosures.