How Did KRAS Become an Actionable Target in Oncology?

In part 1 of a 2-part interview with CancerNetwork®, Frank McCormick, PhD, discussed the technical hurdles that made KRAS resistant to drug development for many years, the origins and impact of the National Cancer Institute's (NCI’s) RAS Initiative, and his reaction to the phase 3 RASolute-302 (NCT06625320) data showing that daraxonrasib nearly doubled overall survival (OS) compared with standard of care in pancreatic cancer.¹ He also spoke about anticipated resistance mechanisms to KRAS, the emerging combination treatment landscape, and the specific trials he is following most closely.

Frank McCormick, PhD, is a professor in the Helen Diller Family Comprehensive Cancer Center and holds the David A. Wood Distinguished Professorship of Tumor Biology and Cancer Research at the University of California, San Francisco (UCSF). He has researched KRAS for 40 years and helped lead the NCI RAS Initiative. He was recently named the inaugural recipient of the Stephenson Global Prize from the Stephenson Global Pancreatic Cancer Research Institute.

CancerNetwork: KRAS was considered undruggable for many years. What was it that made it so resistant to conventional drug development strategies, and what changed?

McCormick: First, I'll say that personally, I never thought KRAS was undruggable. I knew it was difficult, but “undruggable” sounds defeatist. I felt, as many people have felt, that it was just a question of getting the technology to the point where we could actually take on such a difficult target.

It's not the biology that makes it difficult; it's the chemistry of the protein itself. Unlike many other proteins that are targeted for cancer therapy, KRAS doesn't have any obvious pockets where a drug can bind. It's been described as a squishy tennis ball, so it doesn't have a hole where a drug can fit in and block its function. Finding a way of getting small molecule drugs to interact with a squishy tennis ball was technically very difficult, because the methods just weren't around until relatively recently. People had found compounds previously that bound to the protein, but without a detailed knowledge of the protein, it didn't really go anywhere.

Things picked up in 2012, when a group at Genentech and another group found fragments of chemicals that could bind to the RAS protein, using new technology that was sophisticated. Then [Kevan Shokat, PhD], at UCSF found a way of attacking one particular form of the KRAS protein through an amino acid called cysteine, which is exposed in the protein, and that cysteine could be attacked with a chemical that reacts directly and covalently with it. That gave us a handle on a drug that bound to the protein for the first time. From that, and other parallel approaches, the whole thing just crumbled; more people found ways of getting into the protein, [with] more versions of it. Since that 2012-to-2013-time frame, there are now 30 or 40 different drugs that bind to KRAS in slightly different ways, but all using the same principle. That’s how it's evolved.

You also helped lead the NCI's RAS Initiative. Why was an initiative specifically targeted toward RAS necessary, and what were the 1 or 2 breakthroughs during that effort that represented the biggest shifts in progress?

The RAS Initiative was started by [Harold Varmus, MD], a Nobel laureate who was then head of the National Cancer Institute. He was under a lot of pressure from advocates and patients to try to make better progress in treating pancreatic cancer, which at that point had no therapies at all that could provide any patient benefit. Pancreatic cancer is almost always caused by KRAS, so we decided that by focusing on KRAS, we could potentially make an impact on pancreatic cancer.

Harold basically liberated a group of people…in an NCI-funded project, and said, “We’ve got 50 people here. Let's put them to work on KRAS, finding ways of targeting it.” He asked me to lead that effort. In 2013, I started the leadership of the RAS Initiative, and the goal was to find drugs that target the form of KRAS that causes pancreatic cancer. That form is different from the one Kevan Shokat had already gotten a home run hit on—the cysteine mutant, which causes lung cancer. We started a parallel track and found compounds that bind to the forms of KRAS that cause pancreatic cancer, from our own internal work and inspired by Kevan's work and others who made major contributions to this whole project, in a big team effort. Now we ourselves have developed 3 drugs that are currently in clinical trials for pancreatic cancer, and…the rest of the world has also developed drugs that target KRAS for pancreatic cancer, lung cancer, and colorectal cancer.

You alluded to some of the drugs in clinical trials, but after having spent so long researching KRAS, how profound was it when the RASolute-302 data first dropped, and daraxonrasib nearly doubled OS vs standard of care?

That was obviously a wonderful moment for everybody in the field, and for patients and all those involved in treating pancreatic cancer. Up until that point, the progress made in targeting KRAS had really focused on lung cancer, where it's also a major player, but there were already a lot of drugs that had been successful in lung cancer, targeting different proteins that cause the disease. To have a home run in pancreatic cancer was a real first, because nothing had been done up until that point. Apart from very incremental changes in survival benefit, there had been no impact really until those clinical data came out.

Suddenly, the whole field came to life realizing that targeting pancreatic cancer is really a question of getting the right drug and making it happen in the clinic. There's nothing intrinsically impossible about pancreatic cancer; we just needed the right drug to target the right protein. Daraxonrasib will be the first of a lot of drugs being tested in pancreatic cancer right now, and we can expect them to get more potent, with fewer adverse effects, and to improve the outcome of patients with pancreatic cancer by building on that result. Now it's becoming so crowded in pancreatic cancer that it's hard to get a foothold in the clinical research space, and that's really a huge change. People used to avoid trying drugs in pancreatic cancer because they never worked. Now it's like a stampede of drugs coming into pancreatic cancer.

How did daraxonrasib and its mechanism as a RAS(ON) multi-selective inhibitor achieve this?

The approach that Revolution Medicines took was different from the one Shokat took, and the one we took at the RAS Initiative. It uses a cellular protein to help bring RAS together with the drug, so the drug has a helper to make the whole complex work; it's a slightly different mechanism of action. But it does target the “on” state, which is also true of the next generation of direct KRAS lipids we developed for pancreatic cancer. The forms of KRAS that cause pancreatic cancer are mostly stuck in the “on” state all the time, which makes it even more difficult than the cysteine mutant that causes lung cancer, which tends to cycle between different states. They developed a technology that, with a helper and another cellular protein, brings the drug to KRAS and turns it off. It's different from the rest of the herd of drugs coming down the pipeline, but it still targets KRAS in the “on” state, which is the name of the game in pancreatic cancer.

As more RAS inhibitors move toward clinical use, what resistance mechanisms are you anticipating, and what are some of the strategies for staying ahead of them?

There are different types of resistance events that can happen. Inevitably, tumors will find ways of selecting for mutations in the KRAS protein that no longer bind to the drug; that's a given with any targeted therapy. In this case, they could also find mutations that don't bind to the cellular protein that helps the whole system work. That will happen at some rate. There will usually be pre-existing clones that have mutations in the protein that make them insensitive to the drug from the get-go. The only way around that is to have another drug that uses a slightly different binding modality, so the mutations that are resistant to one drug are not resistant to the other. We've seen that in other paradigms, such as EGFR in lung cancer, where there's now a sequential chain of different drugs with different binding modes to get around that problem. That basically will be solved by having a whole battery of different KRAS drugs with different binding modalities, so you can move from one to the next.

Then the tumor cells can develop mutations downstream from KRAS and therefore become independent of it; that probably will happen at some frequency, but I don't think that's going to be such a major issue. Tumor cells can even undergo what's called a state change, where they differentiate into a different beast that is less KRAS dependent. All those things have already been seen in lung cancer with the [KRAS] G12C drugs, but one can expect durable response rates before these mutations kick in, and by the time they do, we'll hopefully have other drugs that can step in. You need a whole suite of compounds to shut down the tumor effectively. Then there are combinations with KRAS drugs plus other targets that make the KRAS drugs more effective, so you kill more cells up front and get less resistance. This path is well trodden from treating lung cancer and other diseases with targeted therapies, so we have a playbook that we expect to work in pancreatic cancer, and that will play out over the next 5 to 10 years.

What do you think about the emerging KRAS combination landscape, and what principles do you think should guide how these combinations are created?

There are [several] different options. For one thing, when you inhibit KRAS, cells have a kind of response, activating other pathways to compensate for the sudden loss of KRAS, and those help them survive. Targeting those short-term adaptive responses makes the KRAS drugs more effective. Right now, a class of drugs called PI3K pathway inhibitors will be tested to prevent that rebound effect. Then there are other classes of combinations that can hopefully wake up the immune system, and that's the paradigm in lung cancer, where the combinations most likely to be in the front line will be KRAS drugs plus a checkpoint inhibitor. KRAS itself makes cells less visible to the immune system, so in theory, suppressing KRAS should make the tumor cells more visible to the immune system, so drugs that target the immune checkpoint should be more effective. That's a class of combination that is probably the best hope for the future, when the immune system can really kick in, and that gives patients the best hope of having a very long-term, durable response. There are other subsets of combinations that will be tested, but the combinations that make the initial hit more effective, and the combinations that wake up the immune system, are the 2 types of combinations that will be most effective in the near future.

Are there any specific trials you're looking at in pancreatic or lung cancer, or any other solid tumors going through this?

Yes, there are many, including the drugs we developed at the Frederick National Lab in collaboration with BridgeBio Oncology Therapeutics, who did the clinical development arm of our project. They're testing pan-KRAS drugs in combination with PI3K inhibitors, and in combination with checkpoint inhibitors in lung cancer, as are many other groups to be totally upfront—those are the combinations we expect to have the most impact in the near future. But in pancreatic cancer, waking up the immune system turns out to be much more difficult than it is in lung cancer, because the whole environment the tumor cells exist in is immune suppressive. Just getting immune effector cells into the tumor to do their job is a big challenge, more so in pancreatic cancer than other indications, but that is the goal. I think one of the goals is to really hit the tumors hard enough that they start to bring in T cells and other immune effector cells, and then engage the immune system. That's almost essential to even imagine a cure in cancer. You really have to have that immune component that will suppress regrowth of tumors in the long term.

Part 2 of this interview continues with McCormick's vision for preventing KRAS-driven cancers before they start, the differences between KRAS allele subtypes, and his outlook for the field over the next decade.

Reference

1. Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5