---
title: "Mechanisms of Acquired Resistance to daraxonrasib in Pancreatic Cancer and Rational Combination St"
id: "nature-3-acquired-resistance-to-the-ras-on-multi-selective-inhibitor-daraxonrasib-guides"
canonical_url: "https://medichelpline.com/clinical-feed/nature-3-acquired-resistance-to-the-ras-on-multi-selective-inhibitor-daraxonrasib-guides"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Nature Medicine"
source_url: "https://www.nature.com/articles/s41591-026-04537-w"
published_at: "2026-08-11T10:24:20.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Mechanisms of Acquired Resistance to daraxonrasib in Pancreatic Cancer and Rational Combination St
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/nature-3-acquired-resistance-to-the-ras-on-multi-selective-inhibitor-daraxonrasib-guides
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Nature Medicine
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41591-026-04537-w)
- **Published At:** 2026-08-11T10:24:20.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Daraxonrasib is an oral **RAS(ON) multi-selective** tri-complex inhibitor that targets active, GTP-bound KRAS, HRAS and NRAS, with activity against mutant and wild-type variants. - A phase 1/2 trial showed clinical activity of daraxonrasib monotherapy in previously treated, RAS-mutant metastatic pancreatic ductal adenocarcinoma (**PDAC**), leading to a phase 3 confirmatory trial. - Targeted sequencing of >800 genes was performed on paired pretreatment and end-of-treatment circulating tumor DNA from 44 patients in the phase 1/2 study to identify mechanisms of acquired resistance. - Treatment-emergent genomic alterations in the **RAS signaling pathway** were found in 26 of 44 patients (59%). The most frequent alteration was mutant **KRAS amplification** in 16 of 44 patients (36%). - Additional acquired alterations included changes in receptor tyrosine kinase (RTK) genes (4 of 44; 9%), MAPK pathway genes (11 of 44; 25%) and PI3K pathway genes (4 of 44; 9%). - No acquired secondary **KRAS** mutations were observed, a pattern distinct from resistance to KRAS G12C(OFF) inhibitors. - Concordant mechanisms of daraxonrasib resistance (mutant KRAS and MYC amplification, RTK upregulation) were observed or mechanistically established in human and murine preclinical PDAC models. - Preclinical combination strategies guided by these findings showed that combining daraxonrasib with agents targeting DNA damage response, RTKs, or the mutant-selective RAS(ON) G12D inhibitor **zoldonrasib** could avert resistance in models. - Overall, most genomic resistance mechanisms to daraxonrasib act through reactivation of RAS pathway signaling and inform potential combination therapy concepts for further investigation in PDAC.
## Clinical Analysis & Structured Key Points
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Aguirre](https://www.nature.com/articles/s41591-026-04537-w#auth-Andrew_J_-Aguirre-Aff3-Aff4-Aff5) [ORCID: orcid.org/0000-0002-0701-6203](https://orcid.org/0000-0002-0701-6203)[3](https://www.nature.com/articles/s41591-026-04537-w#Aff3),[4](https://www.nature.com/articles/s41591-026-04537-w#Aff4),[5](https://www.nature.com/articles/s41591-026-04537-w#Aff5) [na2](https://www.nature.com/articles/s41591-026-04537-w#na2) & * … * [Mallika Singh](https://www.nature.com/articles/s41591-026-04537-w#auth-Mallika-Singh-Aff1) [ORCID: orcid.org/0009-0003-0234-1589](https://orcid.org/0009-0003-0234-1589)[1](https://www.nature.com/articles/s41591-026-04537-w#Aff1) [na2](https://www.nature.com/articles/s41591-026-04537-w#na2) Show authors [_Nature Medicine_](https://www.nature.com/nm) (2026) [Cite this article](https://www.nature.com/articles/s41591-026-04537-w#citeas) [ Save article ](https://www.nature.com/articles/s41591-026-04537-w/save-research?_csrf=fj1ZbXKjy4bGR9f4_3asUp_v7Ly_PtIt) [ View saved research ](https://www.nature.com/saved-research) ## Abstract Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant _KRAS_ amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary _KRAS_ mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant _KRAS_ and _MYC_ amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation. ## Main Hotspot RAS mutations are among the most prevalent oncogenic drivers in cancer, including in PDAC, non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Mutated RAS is an oncogenic driver in over 90% of PDAC cases[1](https://www.nature.com/articles/s41591-026-04537-w#ref-CR1 "Pant, S., Kar, S., Lin, K. K. & Ahler, E. Frequency and incidence of oncogenic mutations in patients with metastatic pancreatic ductal adenocarcinoma: derived from the real-world evidence database Foundation Medicine Insights. J. Clin. Oncol. 43, 777–777 \(2025\)."),[2](https://www.nature.com/articles/s41591-026-04537-w#ref-CR2 "Lee, J. K. et al. Comprehensive pan-cancer genomic landscape of altered cancers and real-world outcomes in solid tumors. NPJ Precis. Oncol. 6, 91 \(2022\)."). These hotspot mutations stabilize RAS in its active GTP-bound (‘ON’) state, driving increased RAS/MAPK signaling, proliferation, metastasis and immune evasion[3](https://www.nature.com/articles/s41591-026-04537-w#ref-CR3 "Lito, P. KRAS oncoprotein signaling in cancer. N. Engl. J. Med. 392, 296–298 \(2025\)."),[4](https://www.nature.com/articles/s41591-026-04537-w#ref-CR4 "Pereira, F. et al. KRAS as a modulator of the inflammatory tumor microenvironment: therapeutic implications. Cells 11, 398 \(2022\)."),[5](https://www.nature.com/articles/s41591-026-04537-w#ref-CR5 "Molina-Arcas, M. & Downward, J. Exploiting the therapeutic implications of KRAS inhibition on tumor immunity. Cancer Cell 42, 338–357 \(2024\)."). Therefore, broad-spectrum RAS(ON) inhibition holds the potential to benefit a large population of patients with cancers driven by activating RAS mutations[6](https://www.nature.com/articles/s41591-026-04537-w#ref-CR6 "Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 \(2020\)."),[7](https://www.nature.com/articles/s41591-026-04537-w#ref-CR7 "Singhal, A., Li, B. T. & O’Reilly, E. M. Targeting KRAS in cancer. Nat. Med. 30, 969–983 \(2024\)."). Daraxonrasib is a RAS(ON) multi-selective inhibitor that targets the active, GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type (WT) variants[8](https://www.nature.com/articles/s41591-026-04537-w#ref-CR8 "Jiang, J. J. et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers. Cancer Discov. 14, 994–1017 \(2024\)."),[9](https://www.nature.com/articles/s41591-026-04537-w#ref-CR9 "Cregg, J. et al. Discovery of daraxonrasib \(RMC-6236\), a potent and orally bioavailable RAS\(ON\) multi-selective, noncovalent tri-complex inhibitor for the treatment of patient
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