The landmark success of a drug against an ‘undruggable’ cancer is spurring fresh optimism in the quest to treat seemingly untouchable tumour targets.
The experimental drug, daraxonrasib, disarms all three members of the RAS family of proteins, which are linked to some of the deadliest cancers. Designing drugs that target the RAS proteins has been notoriously challenging. But a large clinical trial has found that daraxonrasib nearly doubled survival — from 6.7 months to 13.2 months — in people with a form of advanced pancreatic cancer.
The results were presented to a packed room at the American Society of Clinical Oncology annual meeting in Chicago, Illinois, on 31 May, and published in the New England Journal of Medicine. At the conference, the talk was met with a long standing ovation, says Ecaterina Dumbrava, an oncologist at the University of Texas MD Anderson Cancer Center in Houston. “After more than a decade without major advances in treatment for pancreatic cancer, seeing this is really emotional,” she says.
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That success is raising hopes that other challenging targets might also soon fall. Nature talked to researchers about progress in targeting RAS and other “undruggable” cancer proteins that can’t be bested with conventional approaches.
RAS: locked into overdrive
RAS proteins are molecular on–off switches that help to control cell growth and division. But some mutations leave RAS proteins stuck in the ‘on’ position, which drives tumour growth.
Ideally, a cancer drug would switch these proteins off. But drugs typically work by nestling into deep pockets on the surfaces of proteins, and RAS proteins are unhelpfully smooth.
The first anti-RAS drug was approved in the United States in 2021. It targeted only one mutation in one member of the family, a protein called KRAS. That meant that the drug was suitable only for a fraction of people with RAS-driven cancers, and even those tumours quickly became resistant to it.
Daraxonrasib, by contrast, switches off all three members of the RAS family. In a trial of 500 people with advanced pancreatic cancer, those who received daraxonrasib lived another 13.2 months, compared with 6.7 months for those treated with chemotherapy. Daraxonrasib was developed by Revolution Medicines in Redwood City, California.
Researchers hope that this will be just the starting point. Combining daraxonrasib with other drugs — such as a single-mutation KRAS drug — could produce longer-lasting benefits, says Kevan Shokat, a chemical biologist at the University of California, San Francisco. And future variations on daraxonrasib might be able to reduce its toxicity, he adds. “Sometimes the very first molecule just shows that it’s possible,” he says.
MYC: smooth operator
About 70% of all cancers are fuelled by excessive levels of a protein called MYC. But MYC, like RAS proteins, has a smooth surface, making anchoring drugs there difficult.
Furthermore, cancer-driving mutations in the MYC gene are rarely a straightforward, single change to a DNA base — the kind of mutation that might be easily targeted with a drug. Instead, the gene is sometimes duplicated, or other genetic changes make it more active, resulting in more MYC protein than usual. “MYC is going to be a little more complicated” than targeting KRAS, says Shokat.
One leading approach is an experimental drug called OMO-103, made by Peptomyc in Barcelona, Spain. The drug is a ‘mini protein’ that interferes with MYC’s ability to interact with another protein, and has shown promise in a small trial with 19 participants.
Other researchers are screening large libraries of compounds in search of those that might inhibit specific functions of the protein. At Oregon Health and Science University in Portland, cancer researcher Rosalie Sears and her collaborators are using artificial intelligence to hunt for compounds that bind to the part of MYC that helps to repair damaged DNA — a crucial ability in rapidly dividing tumour cells. And Michael Cole, a cancer researcher at the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire, who has been studying MYC for more than 40 years, is looking for compounds that block MYC’s ability to activate certain other genes.
Cole’s effort got a boost from the first KRAS drug, which was approved around the time that he co-founded a company called cosMYC in Cambridge, Massachusetts, to chase such compounds. Buzz around the KRAS-drug approval helped the firm to raise initial financing, says Ed Feris, cosMYC’s chief executive and co-founder. “Everyone was asking, ‘what can we do next’?” he says. “And people were thinking: MYC.”
p53: restoring the guardian
The protein p53 has been called the guardian of the genome, because of its role in preventing cells with damaged DNA from proliferating. The gene encoding p53 is the most commonly mutated gene in cancer, and a lack of normal p53 can fuel many kinds of tumour.
But it’s much more difficult to design a drug that replaces a disabled or missing protein than it is a drug that inhibits one.
Results of a clinical trial published this year are offering fresh hope. That trial tested rezatapopt, a drug that binds to a pocket on p53 that is created by a cancer-causing mutation called Y220C. The Y220C mutation destabilizes p53; rezatapopt binds to the pocket and restabilizes the protein, restoring its function.
In a small trial involving people with a variety of ‘solid’ tumours, such as ovarian and breast cancers, tumours shrank in about 20% of participants who received rezatapopt. A larger trial is ongoing. Although rezatapopt targets only one p53 mutation, Shokat expects its success to fuel the development of drugs that target other p53 mutations.
“I’m hopeful,” says Dumbrava, who was an author on the rezatapopt study. “Now p53 is the next KRAS.”
ß-catenin: precision medicine
When Michael Kahn first began studying the ß-catenin protein nearly 30 years ago, he saw it as an avenue to treat colorectal cancer. Almost all such cancers have elevated activity in a cellular pathway controlled by ß-catenin and another protein called WNT. Shutting off ß-catenin, he reasoned, could be a straightforward road to treatment.
Decades later, researchers are still trying to safely shut down ß-catenin, which is also implicated in several other kinds of cancer but has a variety of important functions in the body. “That pathway is critical in stem-cell biology from head to toe,” says Kahn, now an emeritus chemist at City of Hope, a cancer-treatment centre and research institute in Duarte, California. “Thinking you could just shut it off was very naive.”
But an ongoing clinical trial of a drug called zolucatetide suggests that it might be possible to disable part of the protein while leaving some of its functions intact. Zolucatetide is a helical chain of amino acids that binds to a part of ß-catenin that is crucial for interacting with some of its molecular partners.
The drug is now in early clinical trials. So far, it is well tolerated and responses to the drug seem to be long-lasting, says Gregory Verdine, a chemist and co-founder of the drug’s developer, Parabilis Medicines in Cambridge, Massachusetts, who also helped to design daraxonrasib. “We have people who have been on this drug for three years,” he says. “It is kicking ass.”
This article is reproduced with permission and was first published on June 1, 2026.
