Cancer Research · global
Cancer Cells Turn Up the Volume on KRAS Signaling: Blood-Based Tracking Reveals Resistance Pathways in Pancreatic Cancer
Among 44 patients whose disease progressed after receiving daraxonrasib, more than half developed new RAS pathway abnormalities; the most common was not a secondary KRAS mutation, but amplification of the existing mutated gene.
KRAS mutations in pancreatic cancer have long been considered difficult to target directly with drugs. Now that inhibitors can finally suppress this oncogenic signal, a new question has emerged: how do tumors reconnect the signal? A study published in *Nature Medicine* used circulating tumor DNA to map the landscape of resistance after daraxonrasib treatment and found that one of the most common strategies adopted by cancer cells is to increase the copy number of the existing mutated KRAS gene.
Daraxonrasib is an oral, multi-selective RAS(ON) inhibitor that targets multiple RAS proteins in their active state. The data came from the multicenter, open-label phase 1/phase 1b RMC-6236-001 trial. The analysis included 44 patients with pancreatic ductal adenocarcinoma who received 160 to 300 milligrams of the drug daily, remained progression-free for more than three months, and subsequently experienced disease progression. The research team compared blood samples collected before treatment and at treatment discontinuation to identify newly emerging tumor genomic alterations.
The results showed that 26 patients, or 59%, had oncogenic abnormalities involving RAS, MAPK, PI3K, MYC, or receptor tyrosine kinases at disease progression. Among them, 16 patients—36% of the entire group—had amplification of the mutant KRAS allele. In other words, cancer cells may not need to alter the drug’s direct binding site; they may instead dilute the inhibitory effect by producing more sources of the existing KRAS signal.
The study found no newly acquired oncogenic secondary KRAS mutations in this group of patients, differing from the resistance patterns observed with some KRAS G12C(OFF)-selective inhibitors. However, other patients developed abnormalities in pathways including MAPK, PI3K, receptor tyrosine kinases, and MYC, indicating that resistance does not follow a single route but arises through multiple methods that converge on reactivating signaling downstream of RAS.
Cell and mouse tumor models further supported this explanation: increasing mutant KRAS expression weakened daraxonrasib activity, while some resistant models also showed enhanced HER2 or other receptor signaling. Based on these findings, the research team tested various combinations, including daraxonrasib with the KRAS G12D-selective inhibitor zoldonrasib, the HER2-targeted antibody–drug conjugate trastuzumab deruxtecan, or amivantamab, which acts simultaneously on EGFR and MET. Some models showed deeper and more durable tumor suppression.
These combinations currently remain supported only by preclinical evidence and cannot be assumed to be equally effective or safe in humans. The 44-person analysis also deliberately selected patients whose disease progressed only after more than three months of treatment and for whom both pre- and post-treatment blood samples could be successfully sequenced. Therefore, 59% is not the incidence of resistance among all patients receiving daraxonrasib. Circulating tumor DNA may also miss tumor subpopulations that release lower amounts into the bloodstream, as well as non-genetic resistance mechanisms.
The practical value of this study lies in breaking down the seemingly vague “failure” after disease progression into testable molecular pathways. Prospective clinical trials are still needed to determine whether repeated monitoring of KRAS amplification or receptor signaling changes during treatment can identify resistance early, and whether selecting combination therapies based on these changes can truly extend patient benefit without imposing an excessively high toxicity burden.