New drugs take aim at one of cancer’s deadliest mutations

## Summary
Cancer drugs are closing in on some of the deadliest mutations This made KRAS an appealing target for cancer drug development: find a drug that could switch it off again, the reasoning went, and it would no longer drive tumour growth. And when chemists finally found compounds that could bind to and disable mutant KRAS, the drugs turned out to be effective for only a short period of time. “In every patient, we see resistance developing,” says Saur. “It’s not a cure.” That resistance came in a variety of forms, including new mutations in the KRAS protein, and activation of other cellular processes that could compensate for the loss of KRAS function 2 . What the data say How protein-slayer drugs could beat some of the cruellest cancers Cancer-fighting immune cells could soon be engineered inside our bodies ‘Dark proteins’ hiding in our cells could hold clues to cancer and other diseases More than one-third of cancer cases are preventable, massive study finds Subjects Cancer Medical research Drug discovery Latest on: Cancer Medical research Drug discovery Why some cancer-fighting immune cells lose their strength inside tumours News 02 APR 26 Huge lung-cancer screening campaign boosts early diagnosis Research Highlight 27 MAR 26 Eye drops made from pig semen deliver cancer treatment to mice News 27 MAR 26 Don’t rush use of lymphatic surgery in Alzheimer’s disease Correspondence 07 APR 26 This method to reverse cellular ageing is about to be tested in humans News Feature 07 APR 26 DNA damage burden causes selective CUX2 neuron loss in neuroinflammation Article 01 APR 26 Why the US needs a unified, mission-based strategy for health innovation Comment 06 APR 26 Super-potent opioids could be safer-than-expected alternatives to conventional painkillers News & Views 01 APR 26 AlphaFold database hits ‘next level’: the AI system now includes protein pairing News 17 MAR 26 Jobs NIH-funded Postdoc and Research Scientist Positions in Cancer and Stem Cell Biology Two NIH-funded postdoc positions are immediately available to study Cancer Biology and Stem Cell Biology in Dr. Shenzhen, Guangdong, China Shenzhen University of Advanced Technology Seeking Global Talents at All Levels - SIAT We find Distinguished PIs, Senior PIs, Junior PIs, Senior Engineer, Junior Engineer, Post-doctoral fellow, Assistant research fellow. 1068 Xueyuan Avenue, Shenzhen 518055 P.

## Article Content
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A form of pancreatic cancer (pictured) is often caused by mutations in the KRAS protein.
Credit: PJD/Science Photo Library
Armed with sophisticated chemistry and fresh approaches to drug design, researchers are closing in on innovative strategies to undermine
a cancer-causing mutant protein
once considered to be ‘undruggable’.
Mutations in a protein called KRAS fuel some of the most lethal cancers. Designing drugs to disable KRAS has proved challenging — but this year, a field accustomed to disappointment has renewed hope. The first clinical trial of a drug that targets one form of mutant KRAS for degradation has shown signs of success
1
. And four large clinical trials are testing another drug that inhibits several different mutant forms of KRAS and related proteins. The first of those studies is expected to report results in the next few months.
It is unlikely that any of these approaches will, by themselves, provide a cure, says Dieter Saur, a gastroenterologist and cancer researcher at the Technical University of Munich in Germany. Instead, the hope is that they can be
combined with one another or with other drugs
to create a regimen that KRAS-mutant cancers cannot escape.
“It’s exciting. So many different things are going on,” says Saur. “The field has completely changed.”
On too long
KRAS belongs to the RAS family of proteins, which have key roles in cell growth and proliferation. Some KRAS mutations lock the protein in an ‘on’ position, leading to the uncontrolled cellular growth that is a hallmark of cancer.
Cancer drugs are closing in on some of the deadliest mutations
This made KRAS an appealing target for cancer drug development: find a drug that could switch it off again, the reasoning went, and it would no longer drive tumour growth. But the protein’s relatively smooth surface posed a challenge to drug developers, who typically design molecules that inhibit a protein by binding to pockets in its surface.
And when chemists finally found compounds that could bind to and disable mutant KRAS, the drugs turned out to be effective for only a short period of time. “In every patient, we see resistance developing,” says Saur. “It’s not a cure.”
That resistance came in a variety of forms, including new mutations in the KRAS protein, and activation of other cellular processes that could compensate for the loss of KRAS function
2
. One hope was that some of this resistance could be avoided if, instead of inhibiting mutant KRAS protein, a drug was able to get rid of it altogether.
Rubbish markers
Enter the degraders, compounds that bind to KRAS and then tether it to another protein, called an E3 ubiquitin ligase. The ligase chemically marks KRAS as cellular rubbish, leading
the cell’s waste-processing machinery to break down the protein
and dispose of it.
It is an intricate process to manipulate, says Kevan Shokat, a chemical biologist at the University of California, San Francisco. “The amount of complexity and gymnastics that has to happen — sometimes your protein can get degraded, sometimes it just can’t,” he says.
Even so, oncologist Wungki Park at the Memorial Sloan Kettering Cancer Center in New York City was drawn to the idea of KRAS degraders. “You can actually re-educate the cell: ‘hey, this is disposable, just remove it’”, he says.
More than one-third of cancer cases are preventable, massive study finds
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doi: https://doi.org/10.1038/d41586-026-01016-7
References
Park, W.
et al.
N. Engl. J. Med
. https://doi.org/10.1056/NEJMoa2600752 (2026).
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Pfaff, P. & Shokat, K. M. Preprint at bioRxiv
https://doi.org/10.64898/2026.03.11.711097
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## Expert Analysis

### Merits
- The first clinical trial of a drug that targets one form of mutant KRAS for degradation has shown signs of success 1 .
- And when chemists finally found compounds that could bind to and disable mutant KRAS, the drugs turned out to be effective for only a short period of time. “In every patient, we see resistance developing,” says Saur. “It’s not a cure.” That resistance came in a variety of forms, including new mutations in the KRAS protein, and activation of other cellular processes that could compensate for the loss of KRAS function 2 .
- What the data say How protein-slayer drugs could beat some of the cruellest cancers Cancer-fighting immune cells could soon be engineered inside our bodies ‘Dark proteins’ hiding in our cells could hold clues to cancer and other diseases More than one-third of cancer cases are preventable, massive study finds Subjects Cancer Medical research Drug discovery Latest on: Cancer Medical research Drug discovery Why some cancer-fighting immune cells lose their strength inside tumours News 02 APR 26 Huge lung-cancer screening campaign boosts early diagnosis Research Highlight 27 MAR 26 Eye drops made from pig semen deliver cancer treatment to mice News 27 MAR 26 Don’t rush use of lymphatic surgery in Alzheimer’s disease Correspondence 07 APR 26 This method to reverse cellular ageing is about to be tested in humans News Feature 07 APR 26 DNA damage burden causes selective CUX2 neuron loss in neuroinflammation Article 01 APR 26 Why the US needs a unified, mission-based strategy for health innovation Comment 06 APR 26 Super-potent opioids could be safer-than-expected alternatives to conventional painkillers News & Views 01 APR 26 AlphaFold database hits ‘next level’: the AI system now includes protein pairing News 17 MAR 26 Jobs NIH-funded Postdoc and Research Scientist Positions in Cancer and Stem Cell Biology Two NIH-funded postdoc positions are immediately available to study Cancer Biology and Stem Cell Biology in Dr.
- Charlottesville, Virginia University of Virginia School of Medicine Global Recruitment of Outstanding Young Talents We are seeking exceptional candidates who qualify for the National Science Fund for Excellent Young Scholars (Overseas) 1068 Xueyuan Avenue, Shenzhen 518055 P.

### Areas for Consideration
- But the protein’s relatively smooth surface posed a challenge to drug developers, who typically design molecules that inhibit a protein by binding to pockets in its surface.

### Implications
- It is unlikely that any of these approaches will, by themselves, provide a cure, says Dieter Saur, a gastroenterologist and cancer researcher at the Technical University of Munich in Germany.
- Cancer drugs are closing in on some of the deadliest mutations This made KRAS an appealing target for cancer drug development: find a drug that could switch it off again, the reasoning went, and it would no longer drive tumour growth.
- And when chemists finally found compounds that could bind to and disable mutant KRAS, the drugs turned out to be effective for only a short period of time. “In every patient, we see resistance developing,” says Saur. “It’s not a cure.” That resistance came in a variety of forms, including new mutations in the KRAS protein, and activation of other cellular processes that could compensate for the loss of KRAS function 2 .
- One hope was that some of this resistance could be avoided if, instead of inhibiting mutant KRAS protein, a drug was able to get rid of it altogether.

### Expert Commentary
This article covers cancer, kras, protein topics. Notable strengths include discussion of cancer. Areas of concern are also raised. Readability: Flesch-Kincaid grade 0.0. Word count: 1039.