RAS

  • Rat sarcoma virus (RAS)
  • Gene locations:
    • KRAS chromosome 12p12.1
    • NRAS chromosome 1p13.2
    • HRAS chromosome 11p15.5

Biology

  • The RAS gene family—comprising KRAS, HRAS, and NRAS—encodes small GTPase proteins that function as molecular switches to regulate cell proliferation, differentiation, and survival.1
  • RAS proteins have a highly conserved G-domain, allowing them to bind guanosine triphosphate (GTP) and guanosine diphosphate (GDP), giving them the ability to toggle the protein between an active and inactive state.1
  • Oncogenic RAS mutations, particularly in KRAS, lead to constitutive activation of downstream signaling pathways such as MAPK/ERK and PI3K/AKT/mTOR, promoting tumorigenesis by circumventing apoptotic signals and cell-cycle checkpoints.1,2
  • Among RAS isoforms, KRAS is most frequently implicated in pancreatic cancer and is considered a key oncogenic driver in pancreatic ductal adenocarcinoma (PDAC).2-4

Etiology & Epidemiology

  • Over 90% of patients with PDAC harbor a RAS driver mutation, with approximately 85% involving a KRAS G12 alteration.1,4
  • In the United States, an estimated 56,000 new cases of RAS-mutant PDAC are diagnosed annually, with more than 51,000 involving KRAS G12X mutations.5
  • The most common KRAS mutations in PDAC are G12D (41%) and G12V (34%), followed by G12R (16%), Q61H (4%), and G12C (~1%).1
  • KRAS mutation carries important prognostic implications in PDAC, with KRAS-mutant tumors associated with significantly shorter median overall survival (mOS) than KRAS wild-type tumors (mOS, 32.1 vs 68.5 months).6,7

Testing

When to Test:

  • Testing for the KRAS mutation (as part of broader molecular profiling) is recommended upon diagnosis of advanced or metastatic PDAC to identify therapeutic targets and guide prognosis and trial enrollment.8

Available Testing Methods:

  • Next-generation sequencing (NGS) is the preferred and most commonly used platform for comprehensive molecular profiling in PDAC. It is the standard of care for detecting KRAS mutations and other actionable alterations and is typically performed on tumor tissue or circulating tumor DNA (ctDNA) from plasma samples.9,10
  • Liquid biopsy (ctDNA) is emerging to detect KRAS mutations. In a University of Texas MD Anderson Cancer Center cohort of 311 PDAC patients, ctDNA testing identified KRAS mutations in 81.2% of metastatic cases and 52.4% of localized cases. KRAS-positive ctDNA was associated with significantly worse mOS (14.5 vs 31.3 months; HR, 2.7, P < .0001).9
  • Real-time quantitative polymerase chain reaction (qPCR) assays target hotspot mutations (typically KRAS codons 12/13) and provide a targeted, cost-effective alternative when NGS is unavailable. However, they may miss rarer KRAS variants.11-13

Guideline Recommendations for Testing8:

  • The NCCN Guidelines (version 2.2025) recommend comprehensive germline testing using multigene panels for all patients with confirmed pancreatic cancer, regardless of age or family history.
  • Somatic molecular profiling—ideally via NGS—is recommended for patients with locally advanced or metastatic disease who are eligible for systemic therapy.
  • Profiling should assess for actionable alterations, including gene fusions (ALK, NRG1, NTRK, ROS1, FGFR2, RET), mutations (KRAS, BRAF, BRCA1/2, PALB2), amplifications (HER2), microsatellite instability–high/deficient mismatch repair, and high tumor mutational burden.
  • RNA-based NGS is preferred for fusion detection.
  • Tumor tissue is preferred for testing, but liquid biopsy (cell-free DNA) may be used if tissue is unavailable.

Targeted Therapy

Targeting RAS:

  • Historically, RAS proteins have been considered undruggable due to their smooth surface, lack of binding pockets, and picomolar affinity for GTP/GDP, which makes competitive inhibition particularly challenging.14
  • Technological advancements—such as tri-complex inhibitor platforms—now allow for direct targeting of the active RAS(ON) state by promoting the formation of a novel tri-complex that effectively disrupts oncogenic signaling.15

FDA-Approved Agents:

  • As of mid-2025, no targeted therapies have been approved specifically for RAS-mutated PDAC. However, two KRAS G12C inhibitors—adagrasib and sotorasib—are recommended in NCCN Guidelines (version 2.2025) as treatment options for patients with KRAS G12C-mutant PDAC.8

KRAS G12C Inhibitors: 

  • Adagrasib16
    • Adagrasib is among the first FDA-approved therapies targeting RAS mutations. While it is not yet FDA-approved for pancreatic cancer, it has received regulatory approval for KRAS G12C–mutated advanced non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) in patients with prior systemic treatment, and is recommended by NCCN guidelines for use in KRAS G12C–mutant PDAC.
    • Mechanism of Action:
      • Adagrasib is an irreversible KRAS G12C inhibitor that covalently binds to the mutant cysteine residue, locking KRAS G12C in its inactive state and selectively inhibiting downstream signaling without impacting wild-type KRAS.
    • Investigational Studies:
      • KRYSTAL17
        • ClinicalTrials.gov: NCT03785249
        • Study Design: Multicohort phase 1/2 study evaluating adagrasib in patients (pts) with advanced solid tumors harboring a KRASG12C mutation, including PDAC.
        • Key Outcomes: Adagrasib demonstrated a 33% objective response rate (ORR) in KRAS G12C-mutated PDAC, with a median progression-free survival (PFS) of 5.4 months and median overall survival (OS) of 8.0 months. The treatment was generally well tolerated, with mostly mild to moderate adverse events.
  • Sotorasib18
    • Although sotorasib is not yet FDA-approved for pancreatic cancer, it has received regulatory approval for previously treated KRAS G12C–mutated advanced NSCLC, and is recommended by NCCN guidelines for use in KRAS G12C–mutant PDAC.
    • Mechanism of Action:
      • Sotorasib covalently binds to the cysteine at position 12 (Cys12) of the inactive (GDP-bound) KRAS G12C mutant, locking it in the off state and inhibiting downstream oncogenic signaling.
    • Investigational studies:
      • CodeBreaK 10019
        • ClinicalTrials.gov: NCT03600883
        • Study Design: Phase 1–2 trial to evaluate the efficacy and safety of sotorasib as monotherapy in patients with KRAS p.G12C–mutated pancreatic cancer.
        • Key Outcomes: In the pancreatic cancer cohort, sotorasib demonstrated a confirmed ORR of 21%, a PFS of 4 months, and a median overall survival of 6.9 months.19

Other Investigational Agents:

  • Multi-RAS Inhibitors:
    • Daraxonrasib (RMC-6236)20
      • On June 23, 2025, the FDA granted Breakthrough Therapy Designation to daraxonrasib, a RAS(ON) multi-selective inhibitor for previously treated metastatic PDAC in patients with KRAS G12 mutations.
      • Mechanism of action:
        • Daraxonrasib is a multiselective RAS(ON) inhibitor that selectively binds to the active, GTP-bound form of mutant RAS proteins by forming a complex with cyclophilin A (CypA). This interaction blocks the binding of RAS to downstream effectors, thereby inhibiting oncogenic signaling.
        • Daraxonrasib is unique in that it targets multiple KRAS mutations. including G12(X), G13(X), and Q61(X); it also inhibits other RAS isoforms (eg, NRAS, HRAS).
      • Investigational studies:
        • RASolute 30221
          • ClinicalTrials.gov: NCT06625320
          • Study design: Phase 3, multicenter, open-label, randomized study of daraxonrasib versus investigator's choice of standard of care therapy in patients with previously treated, metastatic PDAC. The study design focuses on a core population of patients with PDAC harboring RAS mutations at position 12 (RAS G12X).
          • Endpoints: The dual primary endpoints for the study are progression-free survival (PFS) and overall survival (OS) in the core patient population.
        • Phase 1 trial23
          • ClinicalTrials.gov: NCT05379985
          • Study design: Phase 1/1b, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, and clinical activity of escalating doses of RMC-6236 in adult patients with advanced solid tumors harboring specific RAS mutations
          • Key outcomes: At the phase 3 dose (300 mg once daily), daraxonrasib demonstrated promising clinical activity in patients with KRAS G12-mutant, metastatic PDAC, with an ORR of 29%, median PFS of 8.5 months, and median OS of 14.5 months.
  • KRAS G12D Inhibitors
    • Zoldonrasib (RMC-9805)24,25
      • Zoldonrasib has not received FDA approval for the treatment of advanced PDAC, but it appears promising in clinical trials. It has not received any FDA-expedited designations.
      • Mechanism of action:
        • Zoldonrasib is a tri-complex RAS(ON) inhibitor with selectivity for KRAS G12D mutants.
        • It covalently binds to the cysteine residue within the switch II pocket of the active, GTP-bound KRAS G12D protein, locking it into an inactive GDP-bound conformation.
        • This prevents KRAS from interacting with downstream effector proteins, thereby halting oncogenic signaling pathways.
      • Investigational studies:
        • Phase 1 study25
          • ClinicalTrials.gov: NCT06040541
          • Study design: Open-label, multicenter, phase 1/1b study of RMC-9805, a selective and orally bioavailable KRAS G12D(ON) inhibitor, in subjects with KRAS G12D–mutant solid tumors to evaluate the safety, tolerability, pharmacokinetics, and preliminary clinical activity
          • Key outcomes: Zoldonrasib demonstrated a 30% ORR and 80% DCR in patients with KRAS G12D–mutant PDAC at the recommended dose of 1200 mg once daily, with no dose-limiting toxicities or treatment discontinuations due to adverse events.
    • GFH375 (VS-7375)26
      • On July 24th, GFH375 received FDA Fast Track Designation as an oral KRAS G12D (ON/OFF) inhibitor for the treatment of KRAS G12D-mutated locally advanced or metastatic PDAC, both in the first-line setting and in patients who have received at least one prior line of systemic therapy.
      • Mechanism of Action:
        • GFH375 is a selective KRAS G12D inhibitor targeting both “ON” (GTP-bound) and “OFF” (GDP-bound) states of KRAS proteins.
      • Investigational Studies:
        • Phase I/II study27
          • ClinicalTrials.gov: NCT06500676
          • Study Design: Multicenter, open-label, phase I/II study to explore the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of GFH375 in patients with advanced solid tumors harboring a KRAS G12D mutation.
    • LY39626732828
      • In KRAS G12D patient-derived xenograft models, LY3962673 demonstrated potent, dose-dependent tumor growth inhibition both as a single agent and in combination with other agents.
      • Mechanism of Action:
        • LY3962673 is a potent, orally bioavailable, noncovalent inhibitor that specifically targets the GDP-bound KRAS G12D mutant.
        • It shows high selectivity for KRAS G12D over wild-type KRAS and other RAS isoforms/mutations.
      • Investigational Studies:
        • MOONRAY-012828
          • ClinicalTrials.gov: NCT06586515
          • Study Design: A phase 1a/1b trial assessing the safety, tolerability, and antitumor activity of LY3962673 as monotherapy and in combination with other chemotherapy agents in participants with KRAS G12D-mutant advanced solid tumor types.

References

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  2. Nusrat F, Khanna A, Jain A, et al. The clinical implications of KRAS mutations and variant allele frequencies in pancreatic ductal adenocarcinoma. J Clin Med. 2024;13(7):2103. doi:10.3390/jcm13072103
  3. Zhang Z, Zhang H, Liao X, Tsai H. KRAS mutation: the booster of pancreatic ductal adenocarcinoma transformation and progression. Front CellDevBiol. 2023;11:1147676. doi:10.3389/fcell.2023.1147676
  4. Stålberg SM, Silwal-Pandit L, Hamfjord J, et al. Elevated KRAS protein level is associated with better survival in pancreatic cancer. BMC Cancer. 2025;25(1):1080. doi:10.1186/s12885-025-14461-w
  5. Pant S, Ahler E, Kar S, Lin KK. Prevalence of oncogenic RAS mutations in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) derived from the real-world evidence Database FoundationCORE. Revolutionary Medicines.  January 25, 2025. Accessed July 23, 2025. https://www.revmed.com/wp-content/uploads/2025/01/2025-ASCO-GI-Mutation-Frequency-poster-13Jan2025-FINAL-for-uploading.pdf
  6. Leiting JL, Alva-Ruiz R, Yonkus JA, et al. Molecular KRAS ctDNA predicts metastases and survival in pancreatic cancer: a prospective cohort study. Ann Surg Oncol. 2025;32(6):4453-4463. doi:10.1245/s10434-025-17036-y
  7. Yousef A, Yousef M, Chowdhury S, et al. Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma. NPJ Precis Oncol. 2024;8(1):27. doi:10.1038/s41698-024-00505-0
  8. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2025. Accessed July 21, 2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  9. Yousef M, Yousef A, Hurd MW, et al. KRAS mutation detection by liquid biopsy for pancreatic ductal adenocarcinoma. JHematol Oncol. 2025;18(1):44. doi:10.1186/s13045-025-01696-0
  10. Kim M, Shim HS, Kim S, et al.  Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP. JPathol Transl Med. 2024;58(4):147-164.doi:10.4132/jptm.2023.11.01
  11. What is real-time PCR (qPCR)? Bio-Rad. Accessed July 23, 2025. https://www.bio-rad.com/en-us/applications-technologies/what-real-time-pcr-qpcr?ID=LUSO4W8UU
  12. Biase D, Visani M, Baccarini P, et al. Next generation sequencing improves the accuracy of KRAS mutation analysis in endoscopic ultrasound fine needle aspiration pancreatic lesions. PLoS One. 2014;9(2):e87651. doi:10.1371/journal.pone.0087651
  13. QClamp KRAS mutation detection tests. Improved sensitivity for single gene mutation detection. DiaCarta. February 7, 2023. Accessed July 1, 2025. https://www.diacarta.com/products/qclamp-gene-mutation-detection-tests/kras/
  14. Healy FM, Prior IA, MacEwan DJ. The importance of Ras in drug resistance in cancer. Br JPharmacol. 2022;179(12):2844-2867.doi:10.1111/bph.15420
  15. Su W, Hou X. Targeting active RAS with molecular glue. Pharm Sci Adv. 2024.2:100047. doi: 10.1016/j.pscia.2024.100047
  16. KRAZATI (adagrasib). Prescribing information. Bristol-Myers Squibb Company, 2024. Accessed July 24, 2025. https://packageinserts.bms.com/pi/pi_krazati.pdf
  17. Bekaii-Saab TS, Yaeger R, Spira AI, et al. Adagrasib in advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(25):4097-4106. doi: 10.1200/JCO.23.00434.
  18. LUMAKRAS (sotorasib). Prescribing information. Amgen, Inc., 2025. Accessed July 22, 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Lumakras/lumakras_pi_hcp_english.pdf
  19. Strickler JH, Satake H, George TJ, et al. Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer.N EnglJ Med. 2023;388(1):33-43.doi: 10.1056/NEJMoa2208470.
  20. Revolution Medicines announces FDA breakthrough therapy designation for daraxonrasib in previously treated metastatic pancreatic cancer with KRAS G12 mutations. Revolution Medicines. June 23, 2025. Accessed July 14, 2025. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy/
  21. Cregg J, Edwards AV, Chang S, et al. Discovery of daraxonrasib (RMC-6236), a potent and orally bioavailable RAS(ON) multi-selective, noncovalent tri-complex inhibitor for the treatment of patients with multiple RAS-addicted cancers. J Med Chem. 2025;68(6):6064-6083. doi:10.1021/acs.jmedchem.4c02314
  22. Brian W, Wainberg ZA, Garrido-Laguna I, et al. Abstract TPS4230: trial in progress - RASolute 302: a phase 3, multicenter, global, open-label, randomized study of daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor, versus standard of care chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). Revolution Medicines.  May 30, 2025. https://www.revmed.com/wp-content/uploads/2025/06/ASCO-2025-RASolute-TiP-Poster.pdf
  23. Garrido-Laguna I, Wolpin BM, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2025;43(4):722. doi: 10.1200/JCO.2025.43.4_suppl.722
  24. Parker J. AACR 2025 | Zoldonrasib demonstrates promising clinical benefit for KRAS G12D-mutated NSCLC. Oncology Central. April 30, 2025. Accessed July 16, 2025. https://www.oncology-central.com/aacr-2025-zoldonrasib-demonstrates-promising-clinical-benefit-for-kras-g12d-mutated-nsclc/
  25. Spira A, Papadopoulos K, Kim D, et al. Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors. J Clin Oncol. 2025;43(4):724. doi:10.1200/JCO.2025.43.4_suppl.724
  26. Verastem Oncology Granted Fast Track Designation for VS-7375 for the Treatment of KRAS G12D-mutated Locally Advanced or Metastatic Pancreatic Cancer. Press Release. Published July 24, 2025. Accessed July 24, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-granted-fast-track-designation-vs-7375
  27. Pachter JA, Yan F, Coma S, et al. GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models. Cancer Res. 2025;85(8_supp_1):4394. doi: 10.1158/1538-7445.AM2025-4394Lakhani
  28. Lakhani NJ, Melisi D, Subbiah V, et al. MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D-mutant solid tumors. J Clin Oncol. 2025;43(4):TPS845. doi: 10.1200/JCO.2025.43.4_suppl.TPS845