This is one of the most amazing things I’ve ever seen. A room full of cancer doctors, on their feet, applauding the full results of a new cancer trial [1][2] — one with the potential to open a new treatment strategy for as many as 20% of all cancers.
The trial involved a novel treatment for pancreatic cancer, one of the deadliest cancers there is. It’s the only major cancer where fewer than one in five people are still alive five years on [3].
And here’s the strange part. The target this drug goes after was, for forty years, written off as impossible to hit — a gene so slippery that researchers gave it a nickname: undruggable [4]. Yet that same gene drives about nine in ten pancreatic cancers [5], and it belongs to a family of genes, called RAS, that’s mutated in nearly one in five cancers of any kind [6]. This previously ‘undruggable’ pathway sits behind a huge share of human cancer.
Table of Contents
- The Gene No Drug Could Touch
- A Glimpse of Hope — And the Wrong Door
- A New Strategy, and the Verdict
- What This Breakthrough Really Means
- References
The Gene No Drug Could Touch
If the stakes are this high, why did it take forty years to fix? This pathway was first found all the way back in 1982. Scientists studying cells from a human bladder tumour found something that rewrote cancer biology: a single typo in the DNA — one wrong letter out of three billion — was enough to turn a normal gene into one that drives cancer [7]. That gene belonged to a small family called RAS [4]. It encodes a class of proteins that control cell growth, division, and survival [8].
One member of that family, KRAS, is the engine of pancreatic cancer — switched on in more than nine out of ten cases [5]. And pancreatic cancer is about as brutal as cancer gets: only around thirteen percent of patients are alive five years after diagnosis [3].
But there’s a huge problem when it comes to designing targeted therapies for KRAS. Its protein is almost perfectly smooth — like a featureless marble. There’s no pocket on its surface, no keyhole for a drug to fit into [9]. So for decades, the attempts failed, and the field hung that label on it: undruggable [4].
So how do you drug a protein with no keyhole?
A Glimpse of Hope — And the Wrong Door
The first crack in the ‘undruggable’ reputation came in 2013, from a lab that refused to believe the surface was truly smooth. A scientist named Kevan Shokat and his colleagues found that one specific version of the mutation — called G12C — briefly opens up a tiny pocket that had never shown up in any picture of the protein before [9]. Suddenly, there was a keyhole. Chemists designed drugs that slip into that pocket and lock the protein in its ‘off’ state [9].
The first of these drugs, sotorasib, was approved in 2021 — the first approved drug to directly target the G12C version of the KRAS mutation [10]. A second, adagrasib, followed the next year [11]. For lung cancer, where the G12C version turns up more often, these were genuine breakthroughs.
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Get Your Personalized Health PlanBut here’s the cruel catch. That pocket only opens on the G12C version. And pancreatic cancer almost never has G12C — it’s overwhelmingly a different mutation, called G12D. Among KRAS-mutated pancreatic tumours, G12C accounts for just one percent [8]. The breakthrough had cut a key — but for a door the cancer that needed it most almost never has.
A New Strategy, and the Verdict
Here’s the idea that changed everything — and earned the applause at the start: stop trying to pick each individual mutation’s lock. Instead of forcing a drug onto the smooth surface of the KRAS protein, scientists came at the problem from a different direction. The new drug grabs a protein the cell already makes in abundance — called cyclophilin A — and hooks onto it first, forming a new molecule. That new molecule then clamps onto RAS proteins while they’re switched on, shutting down the signal they would otherwise send for cells to keep multiplying [5].
And because it works through that borrowed protein instead of a mutation-specific pocket, it isn’t fussy about which version it’s facing. It shuts down G12D — the pancreatic version — along with the others, and even normal RAS that’s stuck on [5].
The drug is called daraxonrasib. The trial that put it to the test was the one that got the standing ovation. It included five hundred patients across six countries, all with metastatic pancreatic cancer that had already come back after chemotherapy — about as grim a setting as oncology has. Half got daraxonrasib as an oral pill; half got more chemotherapy, the current standard of care [5].
Then they measured the thing that matters most: how long did people with this deadly cancer live? Those in the chemotherapy group lived a median of 6.6 months. The patients on daraxonrasib lived 13.2 months [5].
Adding another six months of life doesn’t sound like much — so why the standing ovation? The ovation was for what this trial represents, and what it means for the future of cancer therapies. It shows you can drug the active state of RAS itself — proof of concept that this gene can finally be effectively targeted [5].
What This Breakthrough Really Means
And that’s why the room stood up. Because KRAS isn’t only a pancreatic gene. The same gene drives about half of colorectal cancers and roughly a third of lung cancers [8]. And the RAS gene family, of which KRAS is a part, stands behind nearly 20% of all cancers [6]. A drug that can reach the active state of RAS, regardless of the exact mutation, could matter far beyond the pancreas — and it’s already being tested in lung cancer [12].
It’s also being combined with other therapies, and this is where it gets really exciting. Daraxonrasib doesn’t have to work alone. A company called Tango Therapeutics recently reported the first results of pairing it with a second drug that attacks the cancer through a completely different weakness: many pancreatic tumours are missing a gene called MTAP, and that loss leaves them leaning hard on another protein to survive — so you block that one too. Two independent attacks at once. In a small, early trial of heavily pre-treated patients, the combination shrank tumours in 11 of 12 people, and nine in ten were still progression-free at six months [13]. It’s very early, but the signal is striking.
This breakthrough feels like the dominoes are starting to fall for cancer treatments. For a gene that spent forty years labelled undruggable — one that sits behind roughly one in five cancers — that is a remarkable place to be.
Which Health Risks Should You Focus On Right Now?
Breakthroughs like this one take decades — but the biggest wins for most of us come from getting the basics right. Health Roadmap turns your numbers into a personalized, evidence-based plan for what to prioritize today.
Get Your Personalized Health PlanReferences
1. https://x.com/DrSamuelBHume/status/2061225858384248845/video/1
4. https://www.nature.com/articles/s41392-021-00780-4
5. https://www.nejm.org/doi/full/10.1056/NEJMoa2605555
6. https://pmc.ncbi.nlm.nih.gov/articles/PMC7367715/
7. https://www.nature.com/articles/300149a0
8. https://www.cancerbiomed.org/content/22/7/762
9. https://www.nature.com/articles/nature12796
