New Weakness Found in Pancreatic Cancer Cells

For decades, RAS was considered an untargetable target in oncology. However, with the development of drugs such as sotorasib and adagrasib, and more recently, daraxonrasib, a RAS(ON) inhibitor targeting active mutant and wild-type RAS, the situation is changing. The implications are particularly significant in pancreatic cancer, where more than 90% of tumors harbor RAS mutations.

At this year’s ASCO meeting, landmark Phase III daraxonrasib results in metastatic disease drew a rare 42-second standing ovation—a striking response in a cancer where therapeutic progress has historically come in small increments. But even a promising cancer drug does not work for every patient, and many tumors eventually begin growing again.

A new study published in Nature Medicine shows that cancers that daraxonrasib initially knocked down but that subsequently figured out how to get back up, can reveal what happens next in the RAS revolution. The researchers looked at the progression of events within pancreatic cancer from the start of RAS inhibition until its escape.

They analyzed paired circulating tumor DNA (ctDNA) samples collected before treatment and at progression from 44 patients with RAS-mutant metastatic PDAC treated with daraxonrasib. These were not primary nonresponders. Every patient had initially experienced a complete response, partial response, or stable disease lasting more than three months before eventually progressing.

Mutant KRAS in their blood also declined early during treatment, consistent with daraxonrasib initially suppressing their cancers. When they examined what had changed by the time those cancers progressed, a striking pattern emerged. Twenty-six of the 44 patients—59%—had acquired genomic alterations involving the RAS signaling network.

Most notably, 16 patients, or 36%, acquired amplification of mutant KRAS. Others developed alterations involving RAF, receptor tyrosine kinases (RTKs), or PI3K signaling. In effect, many tumors responded to RAS inhibition by finding ways to turn RAS signaling back up. KRAS amplification was particularly revealing, as tumors made additional copies of the mutant KRAS they already carried.

In laboratory models, increasing mutant KRAS expression increased downstream ERK signaling and progressively reduced sensitivity to daraxonrasib. That represents a notable difference from some earlier KRAS inhibitors, which target KRAS G12C in its inactive, GDP-bound—or RAS(OFF)—state.

No secondary KRAS mutations were detected in the 44 pancreatic cancer patients in the new study. Instead, resistance largely converged on a broader principle: restore enough RAS pathway activity to overcome the drug. This may strengthen the rationale for targeting RAS rather than weaken it.

These cancers appear so dependent on the pathway that, under therapeutic pressure, many evolve specifically to reactivate it. The observation also provided researchers with a roadmap for potential combination therapies. In some models, daraxonrasib treatment increased HER2 expression on the tumor cell surface.

Researchers exploited that vulnerability by combining the RAS inhibitor with the HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd). The combination produced sustained tumor regressions across several pancreatic cancer models, including those with acquired daraxonrasib resistance.

Combining daraxonrasib with amivantamab, a bispecific antibody targeting EGFR and MET, similarly improved the depth and duration of responses in an RTK-driven model. But perhaps the most intriguing strategy was simply to hit RAS harder, by combining daraxonrasib’s broad RAS(ON) inhibition with zoldonrasib.

Zoldonrasib is Revolution Medicines’ mutant-selective RAS(ON) inhibitor targeting KRAS G12D—one of the most common KRAS mutations in pancreatic cancer. The logic is essentially pharmacological double coverage: daraxonrasib suppresses active mutant and wild-type RAS broadly, while zoldonrasib concentrates additional pressure on the principal oncogenic driver.

In treatment-naive mouse models, that doublet produced deeper RAS pathway suppression and substantially delayed progression compared with either drug alone. More importantly, the combination prevented resistance from emerging during the experiments.

The first generation of direct KRAS inhibitors established that the supposedly untargetable protein could, in fact, be targeted. Mutation-selective RAS(ON) inhibitors such as zoldonrasib are expanding the number of individual RAS mutations that can be attacked, while multi-selective agents such as daraxonrasib are attempting to suppress a much broader spectrum of RAS-driven cancers.

Now those approaches may begin converging—through combinations of broad- and mutation-selective RAS inhibitors, or RAS drugs paired with therapies aimed at the escape routes tumors reveal under treatment. Important issues remain, and the researchers found candidate genomic explanations for resistance in roughly 60% of patients, leaving about 40% unexplained.

Nongenomic mechanisms, tumor heterogeneity, and alterations beyond those captured by the ctDNA assay could all contribute, and larger cohorts with paired tumor biopsies will be needed to complete the resistance map. But the study also reveals something fundamental about pancreatic cancer biology.

When daraxonrasib successfully suppresses RAS, many tumors do not simply abandon the pathway and adopt an entirely different means of survival. Instead, they amplify mutant KRAS, activate upstream receptors, or otherwise restore signaling through the same oncogenic circuitry. In that sense, resistance may be further evidence of just how dependent these cancers remain on RAS.

Daraxonrasib helped crack one of cancer biology’s most notoriously difficult targets. The next phase of the RAS revolution will be figuring out how to keep it cracked, and the study suggests that the next leap may come not from moving beyond RAS, but from doubling down on it, using real-time diagnostics to monitor the disease.

As researchers continue to explore the potential of RAS inhibitors, they may also consider combining them with other therapies, such as cell therapy, to achieve even better results.