A new study published in Nature Medicine has provided the first comprehensive characterization of acquired genomic resistance to daraxonrasib, an investigational RAS(ON) multi-selective inhibitor, in patients with pancreatic ductal adenocarcinoma (PDAC).
The study, led by Ida Aronchik, Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick Pui Lai and colleagues, examined circulating tumor DNA from patients with RAS-mutant metastatic PDAC who initially benefited from daraxonrasib before ultimately experiencing disease progression.
The findings reveal that resistance frequently develops through renewed activation of RAS pathway signaling, with mutant KRAS amplification emerging as the most common genomic resistance mechanism. The investigators also identified several potential combination strategies that delayed or overcame resistance in preclinical models.
The study was published on August 11, 2026.
Daraxonrasib Targets RAS in Its Active State
RAS mutations are among the most common oncogenic drivers across cancer, particularly in PDAC, where mutated RAS is present in more than 90% of cases.
Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor designed to target the active, GTP-bound forms of KRAS, HRAS and NRAS, including both mutant and wild-type variants.
The drug is being evaluated across several clinical trials, including a phase 1/2 study in previously treated patients with advanced RAS-mutant tumors.
Previous results from that study showed antitumor activity among patients with metastatic PDAC receiving daraxonrasib as second-line treatment at 300 mg daily. Among 38 patients in the second-line RAS-mutant population, median progression-free survival was 8.1 months, while median overall survival reached 15.6 months.
The clinical activity of daraxonrasib has also formed the basis for evaluation in the randomized phase 3 RASolute 302 trial.
However, despite initial responses, many patients eventually develop progressive disease. Understanding how tumors escape RAS(ON) inhibition therefore represents an important step toward developing strategies capable of producing more durable disease control.
ctDNA Reveals Resistance in More Than Half of Patients
Investigators analyzed paired circulating tumor DNA samples collected before treatment and at disease progression from 44 patients with RAS-mutant metastatic PDAC enrolled in the phase 1/2 study.
Patients had received daraxonrasib at doses of 160–300 mg daily as second-line or later therapy and had experienced either a complete response, partial response or stable disease lasting more than three months before subsequently progressing.
Targeted sequencing covering more than 800 genes identified acquired oncogenic alterations in 26 of 44 patients, or 59%.
Most of these alterations involved pathways capable of restoring or increasing RAS signaling.
The investigators identified alterations involving:
- RAS signaling
- MAPK signaling
- receptor tyrosine kinases
- PI3K/mTOR signaling
- MYC and other oncogenic pathways
Importantly, 11 of 44 patients, or 25%, developed more than one acquired alteration, demonstrating that several resistance mechanisms can emerge simultaneously within the same disease.
KRAS Amplification Emerges as the Dominant Escape Route
The most frequent genomic resistance mechanism was amplification of the existing mutant KRAS allele.
Acquired KRAS amplification was detected in 16 of 44 patients, or 36%, representing 62% of the putative RAS pathway genomic resistance mechanisms identified in the study.
The degree of KRAS amplification varied considerably, ranging from 2.21 to 28.36 copies at progression.
Longitudinal ctDNA analysis provided additional evidence linking KRAS amplification with resistance.
Patients initially demonstrated reductions in mutant KRAS variant allele frequency after starting daraxonrasib. At progression, however, mutant KRAS levels increased again alongside the appearance of newly acquired KRAS amplification.
In one patient, KRAS amplification was detectable in ctDNA one treatment cycle before radiological progression and was subsequently confirmed through sequencing of a tumor biopsy obtained at progression.
Analysis of all 16 patients with acquired KRAS amplification indicated that it was the pre-existing mutant KRAS allele, rather than the wild-type allele, that had become amplified.
TP53 Alterations Were Linked to Acquired KRAS Amplification
The investigators also examined whether baseline genomic features were associated with the later development of KRAS amplification.
TP53 mutations were the most common co-alterations in the cohort, identified in 31 of 44 patients, or 70%.
A significant relationship emerged between pretreatment TP53 alterations and acquired KRAS amplification.
Among patients with pretreatment oncogenic TP53 mutations, 15 of 32, or 47%, subsequently developed KRAS amplification. By comparison, KRAS amplification developed in only 1 of 12 patients, or 8%, with pretreatment wild-type TP53.
The difference was statistically significant, with a P value of 0.03.
No significant association was identified between acquired KRAS amplification and pretreatment alterations in SMAD4, CDKN2A, ARID1A or CHEK2.
Resistance Extended Beyond KRAS
KRAS amplification was not the only mechanism identified.
RAF gene alterations occurred in 5 of 44 patients, or 11%, including alterations involving ARAF, BRAF and RAF1.
Receptor tyrosine kinase alterations were detected in 4 of 44 patients, or 9%, including HER2/ERBB2 amplification, MET alterations and FGFR1 fusion.
Alterations involving the PI3K/mTOR pathway were also identified in 4 of 44 patients, or 9%, affecting genes including PIK3CA, AKT1, AKT2, RICTOR and PIK3R1.
Other acquired changes included truncating NF1 mutations, KEAP1 alterations, a PTPN11 mutation and MYC amplification.
Together, these alterations largely converged on a common biological consequence: reactivation or intensification of RAS pathway signaling despite continued RAS inhibition.
A Different Resistance Pattern From KRAS G12C Inhibitors
One of the most notable findings was what investigators did not observe.
No acquired secondary-site KRAS mutations were detected in the 44 patients with PDAC.
This distinguishes the resistance pattern seen with daraxonrasib from that reported with mutant-selective KRAS G12C(OFF) inhibitors, where secondary KRAS mutations capable of interfering with drug binding can emerge during treatment.
Experimental deep mutational scanning nevertheless demonstrated that several KRAS second-site mutations could theoretically confer resistance to RAS(ON) inhibition, including changes involving E37, Y64, Y71, L56, T58 and R68.
Despite this potential, these secondary mutations were not detected clinically in the PDAC cohort or in the PDAC preclinical models that developed acquired resistance.
No compensatory oncogenic alterations in NRAS or HRAS were identified either.
The findings therefore point toward a resistance landscape dominated primarily by increased pathway signaling and pathway reactivation rather than secondary mutations at the drug-binding target.
Preclinical Models Reproduce the Clinical Resistance Pattern
The investigators subsequently created a series of human and murine PDAC models to determine whether the resistance mechanisms observed in patient ctDNA could directly reduce sensitivity to daraxonrasib.
These models reproduced several of the clinical findings, including:
- mutant KRAS amplification
- MYC amplification
- receptor tyrosine kinase upregulation
- increased downstream RAS/MAPK signaling
Increasing mutant KRAS expression in engineered models raised pERK levels and progressively reduced sensitivity to daraxonrasib.
A resistant HPAC model with acquired KRAS G12D amplification similarly showed increased KRAS protein expression, higher pathway activity and cross-resistance to both daraxonrasib and the KRAS G12D-selective RAS(ON) inhibitor zoldonrasib.
Other resistant models demonstrated increased HER2 expression, MYC amplification, elevated c-MET activity or combinations of these mechanisms.
These findings provided a platform for testing therapies designed specifically around the resistance mechanisms observed in patients.
HER2 Upregulation Creates a Potential Therapeutic Vulnerability
One strategy focused on receptor tyrosine kinases.
Daraxonrasib treatment increased surface HER2 expression in several PDAC models. Investigators hypothesized that this adaptive response could potentially be exploited using the HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd).
Combination treatment with daraxonrasib and T-DXd produced sustained tumor regressions in multiple xenograft models carrying different KRAS mutations, including KRAS G12C, G12R and G12D.
In parental and daraxonrasib-resistant Capan-1 models, the combination produced complete and durable tumor regressions, with responses maintained even after treatment ended.
However, the benefit was not universal.
One model with very low baseline HER2 expression and minimal HER2 induction following daraxonrasib did not demonstrate a meaningful combination effect, suggesting that activity could depend on sufficient HER2 expression, efficient antibody-drug conjugate internalization or baseline sensitivity to the cytotoxic payload.
EGFR and MET Targeting Offers Another Route Around Resistance
The investigators also explored resistance involving c-MET and EGFR.
Because MET alterations were detected in ctDNA from some patients progressing on daraxonrasib, the researchers evaluated daraxonrasib in combination with amivantamab, a bispecific antibody targeting EGFR and MET.
In the KP-4 PDAC model, daraxonrasib alone initially caused tumor regression, followed by tumor regrowth after approximately 14 days.
Combining daraxonrasib with amivantamab significantly improved both the depth and duration of tumor response compared with either treatment alone.
The results support further investigation of RTK-directed therapies as potential partners for RAS(ON) inhibition when resistance involves receptor tyrosine kinase activation.
Combining Two RAS(ON) Inhibitors Delays Resistance
Another strategy directly intensified RAS blockade.
Investigators combined daraxonrasib with zoldonrasib, a mutant-selective RAS(ON) G12D inhibitor.
The rationale was to simultaneously suppress mutant and wild-type RAS signaling more deeply, particularly in tumors where resistance had developed through increased RAS pathway flux.
In treatment-naive KRAS G12D-driven mouse models, the daraxonrasib–zoldonrasib doublet produced deeper tumor responses and significantly prolonged progression-free survival compared with either monotherapy.
Importantly, the upfront combination durably prevented the emergence of resistance in these models.
The combination also demonstrated enhanced antitumor activity in models that had already developed resistance to RAS(ON) monotherapy.
The findings suggest that intensified direct RAS inhibition could potentially be used either before resistance develops or after RAS hyperactivation-mediated resistance has emerged.
DNA Damage Response Pathways Provide an Additional Target
The study also explored combinations involving the DNA damage response pathway.
Because KRAS amplification was associated with TP53 alterations and both KRAS activation and loss of p53 function can create replication stress, investigators evaluated daraxonrasib with inhibitors of the ATR–CHK1–WEE1 axis.
The CHK1 inhibitor BBI-355 and WEE1 inhibitor azenosertib showed activity in experimental models.
In vivo, daraxonrasib combined with azenosertib produced deeper and more durable regressions than either agent alone in the evaluated HPAF-II model, although the combination did not exceed optimal-dose daraxonrasib monotherapy.
The investigators concluded that the DNA damage response machinery represents another therapeutic vulnerability in RAS-mutant PDAC, while noting that the feasibility of these combinations will depend on agents with suitable safety profiles.
Resistance Remains Unexplained in Around 40% of Patients
Despite identifying candidate genomic resistance mechanisms in approximately 60% of the cohort, the study also highlighted an important unresolved group.
Among the 18 patients without an identified putative genomic resistance mechanism, five had no detectable acquired alterations among the more than 800 genes analyzed.
The remaining patients had alterations associated with clonal hematopoiesis or non-recurrent changes whose role in resistance remained uncertain.
The authors therefore noted that approximately 40% of tumors progressing on daraxonrasib could develop resistance through nongenomic mechanisms.
The analysis was also restricted to patients with sufficient circulating tumor DNA shedding, and the sequencing panel could not exclude resistance alterations outside the genes examined.
Larger patient cohorts and paired tumor biopsies will be required to determine the full spectrum of genomic and nongenomic resistance mechanisms and establish whether the resistance alterations identified in the study arise during treatment or were already present in small subclones before therapy.
From Resistance Biology to Rational Combination Therapy
The study provides the first detailed clinical and preclinical assessment of acquired resistance following response to daraxonrasib in PDAC.
Rather than escaping primarily through new secondary KRAS mutations, resistant tumors frequently appeared to restore the very signaling network daraxonrasib was designed to suppress.
Mutant KRAS amplification represented the clearest example, but alterations involving RAF, receptor tyrosine kinases, PI3K signaling and MYC pointed toward the same broader pattern of renewed oncogenic signaling.
Those resistance mechanisms, in turn, identified potential therapeutic vulnerabilities.
The preclinical findings highlighted two particularly actionable approaches: combining daraxonrasib with RTK-directed therapies such as T-DXd or amivantamab, and strengthening direct RAS blockade through a daraxonrasib–zoldonrasib RAS(ON) inhibitor doublet.
The investigators concluded that these findings establish a translational framework for developing combination strategies aimed at preventing or overcoming resistance and extending the therapeutic benefit of RAS-targeted treatment in pancreatic cancer.
Reference: Aronchik I, Kar S, Zhuang Y, et al. Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer. Nature Medicine. Published August 11, 2026.
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