KRAS Inhibitors: A New Class of Targeted Cancer Drugs

KRAS inhibitors are small-molecule drugs that shut down one of the most common cancer-driving proteins in the human body, a protein that scientists spent more than three decades calling “undruggable.” The first two approved drugs in this class, sotorasib and adagrasib, work against a specific version of the KRAS mutation found in roughly 13 to 15 percent of non-small-cell lung cancers. Their approval in the early 2020s broke open what had been one of the longest-standing dead ends in oncology, and the field is now racing to extend the same approach to other KRAS mutations that fuel pancreatic, colorectal, and several additional cancers.

Why KRAS Was Called Undruggable

KRAS is a small signaling protein that acts like a molecular switch. In a healthy cell, it flips between an “on” state and an “off” state, helping relay growth signals from the cell surface to the nucleus. When KRAS picks up certain mutations, it gets stuck in the “on” position, telling the cell to keep dividing regardless of whether it should. That simple malfunction is behind an enormous share of human cancers. Pancreatic ductal adenocarcinoma carries KRAS mutations in roughly 92 percent of cases, colorectal cancer in about 49 percent, and non-squamous non-small-cell lung cancer in around 35 percent.¹

The protein’s surface is smooth and nearly featureless. Most drugs work by wedging themselves into a groove or pocket on a target protein, but KRAS has no obvious pocket deep enough for a drug molecule to grab onto with high affinity. Making matters worse, the mutant protein is almost identical in shape to the normal version of KRAS that every cell needs for healthy signaling, so any drug that blocked all KRAS activity indiscriminately risked serious toxicity.² For more than 30 years, the consensus was that directly drugging KRAS simply could not be done.

The Switch-II Pocket Breakthrough

The turning point came in 2013, when a team led by Kevan Shokat at the University of California, San Francisco discovered a hidden pocket on the KRAS protein that only opens up when the protein carries a specific mutation called G12C. In this mutation, the amino acid glycine at position 12 is swapped for cysteine, and that cysteine has an unusually reactive side chain. Shokat’s group designed a small molecule that latched onto that cysteine through a permanent chemical bond, slipping into the newly identified “switch-II pocket” and locking the protein in its inactive, off state.³ The drug essentially traps KRAS-G12C so it can no longer relay growth signals.⁴

This was a feat of chemical ingenuity. The pocket the drug exploits is not visible in most crystal structures of KRAS; it only appears when the protein is in its inactive conformation. And because the covalent bond targets the mutant cysteine specifically, normal KRAS in healthy cells is largely left alone. That selectivity is what made the whole approach viable.

The First Approved Drugs and Their Clinical Results

Shokat’s proof of concept triggered a pharmaceutical race. Amgen developed sotorasib (sold as Lumakras), which received accelerated FDA approval in 2021 for previously treated KRAS-G12C-mutant non-small-cell lung cancer. Mirati Therapeutics (later acquired by Bristol-Myers Squibb) developed adagrasib (sold as Krazati), which followed with its own approval in 2022.

In a pivotal study of adagrasib, about 43 percent of previously treated lung cancer patients had their tumors shrink meaningfully, and the median time before the cancer progressed was roughly six and a half months. Median overall survival reached about 12.6 months. Among the subset of patients whose cancer had spread to the brain, a third also saw their brain lesions respond to the drug.⁵ When the two drugs were compared indirectly across their respective trials, the outcomes were statistically similar: median progression-free survival of about 6.4 months for adagrasib versus 5.7 months for sotorasib, and median overall survival of 12.6 versus 11.4 months, with no significant difference between them.⁶

These numbers represent real progress for a patient population that previously relied on standard chemotherapy or immunotherapy, but they also show that KRAS inhibitors are not a cure on their own. Most patients eventually see their cancer grow again, which has made understanding resistance and designing smarter combinations the central challenge of the field.

The Colorectal Cancer Problem

One of the sharpest disappointments in early KRAS-G12C inhibitor research was colorectal cancer. The same mutation, the same drug, but a dramatically different response: where lung cancer patients saw tumor-shrinkage rates in the 30 to 40 percent range, colorectal cancer patients managed only about a 3 percent response rate to sotorasib as a single agent.⁷

Researchers traced the problem to EGFR, a receptor on the cell surface that feeds signals into the same pathway KRAS uses. In colorectal cancer cells, EGFR activity is naturally much higher than in lung cancer cells. When a KRAS inhibitor shuts down KRAS, the high baseline EGFR signaling quickly reactivates the growth pathway through alternative routes, producing a rapid rebound that makes the drug ineffective within days.⁸ The same studies showed that pairing a KRAS inhibitor with an EGFR blocker could overcome this resistance in laboratory models, and clinical trials of these combinations in colorectal cancer are ongoing.

The colorectal cancer experience made something clear: a cancer’s tissue of origin shapes how it responds to targeted therapy in ways that go beyond which mutation is present. The signaling environment around KRAS matters as much as the mutation itself.

How Resistance Develops

Even in lung cancer, where the drugs work well initially, resistance is the norm rather than the exception. The mechanisms fall into two broad categories.

The first involves secondary mutations in the KRAS gene itself. In laboratory experiments that generated drug-resistant cell lines, the vast majority of resistant clones had acquired new mutations in KRAS on top of the original G12C change. Researchers identified 12 distinct secondary mutations, with changes at position Y96 (specifically Y96D and Y96S) conferring resistance to both sotorasib and adagrasib.⁹ These secondary mutations physically alter the switch-II pocket or the surrounding protein surface, weakening the drug’s grip.¹⁰

The second category involves bypass signaling. Cancer cells can reactivate growth pathways by turning up activity from receptor tyrosine kinases or amplifying other members of the RAS family. One example involves HER2 amplification in colorectal cancer, which can actually relocalize the KRAS protein away from the cell membrane (where it normally functions) into the cell interior, reducing the cancer’s dependence on KRAS altogether.¹¹ More broadly, upregulation of receptor tyrosine kinase activity can activate the normal, non-mutant copy of KRAS (or related RAS proteins), which then takes over for the blocked mutant and keeps signaling alive.¹²

Beyond G12C: Targeting Other KRAS Mutations

KRAS-G12C accounts for about 15 percent of all KRAS mutations across cancers, which means the first approved drugs are relevant to only a slice of the KRAS-mutant population. The two most common KRAS mutations overall are G12D (roughly 29 percent of cases) and G12V (roughly 23 percent).¹ G12D is especially dominant in pancreatic cancer, where it accounts for about 43 percent of KRAS mutations. Cracking these mutations is arguably the bigger prize.

The challenge is that G12D and G12V do not have the reactive cysteine that made G12C druggable with a covalent approach. Researchers are pursuing noncovalent inhibitors that bind the switch-II pocket through different chemistry, and several G12D-selective small molecules are now in early clinical development, particularly for pancreatic cancer.¹³

An even more ambitious strategy aims at pan-KRAS inhibition: drugs that block multiple KRAS mutant variants simultaneously while sparing the closely related HRAS and NRAS proteins. One example is AM-2383, a reversible inhibitor that binds KRAS in both its active and inactive states and has shown potent tumor suppression in animal models driven by G12D and G12V mutations.¹⁴ Other pan-KRAS inhibitors with activity against multiple mutants and wild-type KRAS are also being developed.¹⁵ These broader-acting drugs would be relevant to a much larger share of cancer patients, but they also raise harder questions about safety, since wild-type KRAS has important roles in normal cells.

New Drug Designs Targeting Active KRAS

The first-generation inhibitors only work when KRAS is in its inactive (GDP-bound) state, which is why they rely on the protein cycling back to “off” before the drug can catch it. But in highly active tumors, KRAS may spend most of its time in the “on” (GTP-bound) state, limiting how much of the protein the drug can reach at any given moment. A newer class of compounds aims to target KRAS while it is active.

Daraxonrasib (RMC-6236) represents a fundamentally different approach called tri-complex inhibition. Instead of fitting into a pocket on KRAS by itself, the drug molecule forms a three-way complex: it simultaneously binds KRAS and a naturally abundant chaperone protein called cyclophilin A. The resulting bulky complex physically prevents KRAS from interacting with its downstream signaling partners, shutting off the growth signal even while the protein is in its active configuration.¹⁶ Daraxonrasib targets multiple RAS variants and is already in clinical trials, generating considerable excitement for cancers where the first-generation approach falls short.

Another emerging strategy uses PROTACs, which are bifunctional molecules designed to physically destroy the target protein rather than merely inhibiting it. A PROTAC links a KRAS-binding element to a tag that recruits the cell’s protein-disposal machinery, causing the cell to chew up and degrade the mutant KRAS protein entirely. Early-stage PROTAC compounds targeting KRAS-G12D have shown the ability to degrade the mutant protein in pancreatic cancer cell lines.¹⁷ Preclinical PROTAC compounds targeting G12C, G12D, and G12V have also been reported.¹⁸ By eliminating the protein altogether, PROTACs could theoretically overcome some forms of resistance that arise when the drug-binding pocket changes shape, since the degradation pathway relies on different parts of the protein surface.

Combination Therapies and Immunotherapy

Given that resistance nearly always develops with single-agent KRAS inhibitors, combination strategies are where much of the field’s energy is focused. One of the most promising pairings involves SOS1 inhibitors. SOS1 is a protein that activates KRAS by helping it swap from the off-state to the on-state. Blocking SOS1 alongside KRAS produces deeper and more durable tumor shrinkage in preclinical models of both lung and colorectal cancer, and can even restore drug sensitivity in tumors that have already become resistant to a KRAS inhibitor alone.¹⁹ This double-blockade approach attacks the pathway from two different angles, making it harder for the cancer cell to find a workaround.²⁰

Immunotherapy combinations represent another active frontier. KRAS-mutant tumor cells create a local environment that suppresses the immune system, so shutting off KRAS signaling can reverse that immune suppression and make the tumor more visible to immune cells. In mouse models, combining KRAS-G12C inhibitors with anti-PD-1 immune checkpoint therapy produced long-term cures in the majority of treated animals, and those cures were shown to depend on a functioning immune system: animals without active T and B cells did not benefit.²¹ Multiple clinical trials are now testing these immunotherapy combinations in patients.²²

Side Effects and Tolerability

Compared with traditional chemotherapy, KRAS-G12C inhibitors are generally well tolerated, but they are not side-effect-free. A meta-analysis pooling data from multiple studies found that about 79 percent of patients experienced some degree of treatment-related side effects, while roughly a quarter had side effects rated grade three or higher (meaning serious enough to affect daily function or require intervention). Sotorasib had a lower rate of both overall and severe side effects compared with adagrasib.²³ The most common issues are gastrointestinal (diarrhea, nausea) and liver enzyme elevations. For patients who also need radiation therapy to the chest, the combination appears manageable: in a study of 42 patients receiving thoracic radiation alongside a KRAS-G12C inhibitor, about a third had moderate side effects and only one developed serious lung inflammation.²⁴

The tolerability difference between the two approved drugs matters in real-world treatment decisions. Adagrasib’s higher side-effect burden translates into greater costs for managing those side effects and more frequent need for anti-nausea and anti-diarrheal medications. A cost-effectiveness analysis from a U.S. payer perspective found that sotorasib was the more economical choice, with total discounted costs running roughly $18,000 lower than adagrasib, driven by differences in drug price, side-effect management, and supportive medications.²⁵ Since the two drugs produce similar survival outcomes, these practical differences in tolerability and cost often influence which one a patient and their oncologist choose.

Finding Patients With KRAS Mutations

You cannot prescribe a KRAS inhibitor without first confirming that a patient’s tumor carries the right mutation, which makes molecular testing the gatekeeper to this entire drug class. Standard practice involves sequencing tumor DNA from a biopsy sample, but liquid biopsy, which detects tumor DNA fragments circulating in the bloodstream, is gaining ground as a less invasive option for identifying KRAS mutations.²⁶

Liquid biopsy has a particular advantage for tracking resistance. When a patient’s cancer progresses on a KRAS inhibitor, the resistance mechanism may be different in different parts of the body. A traditional tissue biopsy only captures what is happening at a single tumor site. In one reported case of colorectal cancer progressing on treatment, blood-based testing identified two different KRAS resistance mutations (Y96S and Y96C) that the original tissue biopsy had never shown.²⁷ This kind of monitoring could become standard for guiding treatment switches as the toolkit of KRAS-targeting drugs expands.

Which Cancers Stand to Benefit Most

The landscape of KRAS mutations varies dramatically from one cancer type to the next, and that variation determines where the next wave of inhibitors could have the greatest impact. Among lung cancers, G12C is the most common KRAS variant, accounting for about 40 percent of KRAS-mutant non-squamous cases, which is why lung cancer was the first proving ground for the approved drugs.¹

Pancreatic cancer is arguably the tumor type with the most urgent need. With roughly 92 percent of cases carrying a KRAS mutation, and G12D being the dominant variant at 43 percent, this cancer is overwhelmingly KRAS-driven. Yet pancreatic cancer has historically been one of the hardest to treat, with very limited targeted therapy options. G12D-selective inhibitors and pan-KRAS drugs now entering clinical trials represent the first realistic chance to target the root driver mutation in most pancreatic cancers. Colorectal cancer also has a high KRAS mutation rate (about 49 percent), but as discussed earlier, intrinsic EGFR-driven resistance complicates single-agent approaches, making combination strategies essential. Gastrointestinal cancers more broadly share a common KRAS mutation profile dominated by G12D and G12V, so drugs targeting those variants could eventually reach patients with cancers of the stomach, small bowel, and appendix as well.

The field is moving quickly enough that the next few years of clinical trial results should reshape treatment options across multiple tumor types. Whether the newer pan-KRAS inhibitors, tri-complex inhibitors, and PROTACs can deliver on their preclinical promise in human patients is the question that will define this drug class’s second chapter.²⁸

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