At Revolution Medicines, Medical Affairs supports US healthcare providers in oncology by sharing rigorous, evidence-based insights related to RAS-driven cancers.
RAS in Cancer
The RAS family of proteins, which includes the canonical members KRAS, NRAS, and HRAS, share significant sequence homology and similar functions.1-4
Normal RAS Signaling
RAS proteins play a crucial role in the regulation of cell proliferation and survival in normal cells.1,2
These proteins function as tightly regulated molecular switches which cycle between an active, GTP-bound [RAS(ON)] state and inactive, GDP-bound [RAS(OFF)] state. Activation is driven by GEF-mediated GDP-GTP exchange, while inactivation is a function of GAP-stimulated hydrolysis of GTP to GDP.1-3,5
When RAS is switched ON, it initiates downstream signaling that promotes cell growth, proliferation, and survival. In normal cells, RAS is predominantly in the OFF state and is only transiently switched ON in response to growth signals before returning to the OFF state. This careful regulation maintains a tight balance between RAS in its OFF and ON states.5,6
RAS in Cancer
Oncogenic mutations which cause amino acid changes at G12, G13, and Q61 in RAS genes can drive cancer initiation and progression by disrupting this balance, resulting in an accumulation of RAS(ON) proteins to drive excessive RAS signaling in tumor cells.1,7 These mutations are common across multiple tumor types and are associated with poor survival outcomes.2,3,6
Why RAS matters in cancer
- RAS mutations are present in approximately one-fifth of human cancers.1
- Oncogenic mutations at amino acids G12, G13, and Q61 of RAS proteins can impair GTP hydrolysis and cause accumulation of RAS(ON), driving cancer initiation and progression.1,7
RAS mutations in cancer
- Cancers commonly driven by RAS mutations include PDAC (~92% RAS mutant), CRC (~50% RAS mutant), and NSCLC (~30% RAS mutant), all of which exhibit a wide array of RAS mutations.1,4,8,9
- RAS is a key oncogenic driver, but there are limited therapeutic options that directly inhibit RAS.10,11
Revolution Medicines’ investigational RAS(ON) inhibitors are orally administered molecules12-15 that enter the cancer cell and bind to cyclophilin A, a naturally abundant cytosolic protein that normally does not interact with RAS.16,17
This binary complex of the RAS(ON) inhibitor bound to cyclophilin A binds to RAS in its ON state, forming an inhibitory tri-complex that can prevent RAS from activating downstream effector proteins in the signaling cascade.16,17
In addition, the investigational RAS(ON) multi-selective inhibitor daraxonrasib can stimulate the intrinsic GTPase activity of RAS(ON) proteins, promoting conversion from the active GTP-bound state to the inactive, GDP-bound RAS(OFF) state (not shown in the figure).18
Inhibiting the function of RAS(ON) can attenuate RAS oncogenic signaling and may cause cancer regression and tumor cell death.16,17 Using this tri-complex inhibitor approach, Revolution Medicines is developing a pipeline of investigational RAS(ON) inhibitors.12,14,19-22
Revolution Medicines Investigational RAS(ON) Inhibitors
Four Investigational RAS(ON) Inhibitors Are in Clinical-Stage Trials for Targeting RAS Mutant Cancers
Daraxonrasib (RMC-6236)
A RAS(ON) multi-selective
noncovalent inhibitor16,22
Current Phase 3 clinical trials include RASolute 302, RASolute 303, RASolute 304, and RASolve 301 Early phase clinical trials include RMC-GI-102, RMC-LUNG-101, RMC-APEX-103, RMC-6236-001, RMC-6291-101, RMC 5127-001, and RMC-9805-00119-21,23-30
Zoldonrasib (RMC-9805)
A RAS(ON) G12D-selective
covalent inhibitor22,31
Current early phase clinical trials include RMC‑GI‑102, RMC-LUNG-101, RMC-APEX-103,
and RMC-9805-00119-21,28
Elironrasib (RMC-6291)
A RAS(ON) G12C-selective
covalent inhibitor22,32
Current early phase clinical trials include
RMC-LUNG-101, RMC-6291-101, RMC-APEX-103, and RMC‑6291‑00121,28,29,33
RMC-5127
A RAS(ON) G12V-selective
noncovalent inhibitor22,34
Current early phase clinical trials include
RMC-5127-00130
Abbreviations
AKT, protein kinase B; CRC, colorectal cancer; CYPA, cyclophilin A; ERK, extracellular signal-regulated kinase; GAP, GTPase-activating protein; GDP, guanine diphosphate; GTPase, guanine triphosphatase; GEF, guanine nucleotide exchange factors; GTP, guanine triphosphate; mCRC, metastatic colorectal cancer; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian Target of Rapamycin; NSCLC, non–small cell lung cancer; P13K, phosphoinositide 3-kinase; PDAC, pancreatic ductal adenocarcinoma; RAF, rapidly accelerated fibrosarcoma kinase; RAS, rat sarcoma.
References
1. Prior IA, Hood FE, Hartley JL. The Frequency of Ras Mutations in Cancer. Cancer Res. 2020 Jul 15;80(14):2969-2974. doi: 10.1158/0008-5472. 2. Singhal A, Li BT, O’Reilly EM. Targeting KRAS in cancer. Nat Med. 2024;30(4):969-983. doi:10.1038/s41591-024-02903-0. 3. Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533–552. doi.org/10.1038/s41573-020-0068-6. 4. Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol. 2022;6(1):91. doi:10.1038/s41698-022-00334-z 5. Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Sig Transduct Target Ther. 2023;8:455. doi.org/10.1038/s41392-023-01705-z. 6. Oya Y, Imaizumi K, Mitsudomi T. The next generation KRAS inhibitors: What comes after sotorasib and adagrasib? Lung Cancer. 2024;194:107886. 7. Chen K, Zhang Y, Qian L, Wang P. Emerging strategies to target RAS signaling in human cancer therapy. J Hematol Oncol. 2021;14(1):116. doi:10.1186/s13045-021-01127-w 8. Tolani B, Celli A, Yao Y, et al. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice. Nat Biotechnol. 2022;40(12):1834-1844. doi:10.1038/s41587-022-01386-z 9. Cascetta P, Marinello A, Lazzari C, et al. KRAS in NSCLC: State of the Art and Future Perspectives. Cancers (Basel). 2022;14(21):5430. doi:10.3390/cancers14215430 10. Liu J, Kang R, Tang D. The KRAS-G12C inhibitor: activity and resistance. Cancer Gene Ther. 2022;29(7):875-878. doi:10.1038/s41417-021-00383-9 11. Yang X, Wu H. RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms. J Hematol Oncol. 2024;17(1):108. doi:10.1186/s13045-024-01631-9 12. Garrido-Laguna I, Wolpin B, 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_suppl): Abstract 722. 13. Koltun E, Lin W. RMC-6236, a RAS(ON) multi-selective tri-complex inhibitor. Presented at: American Association for Cancer Research (AACR) Annual meeting; April 05-10, 2024; San Diego, CA. 14. Hong DS. RMC-9805 is an oral, mutant-selective, covalent inhibitor targeting the ON (active GTP-bound) state of RAS G12D. Presented at: 36th EORTC-NCI-AACR (ENA) Symposium; October 23-25, 2024; Barcelona, Spain. 15. Jänne PA, Bigot F, Papadopoulos K, et al. Preliminary Safety and Anti-Tumor Activity of RMC-6291, a First-In-Class, Tri-Complex KRASG12C(ON) Inhibitor, in Patients With or Without Prior KRASG12C(OFF) Inhibitor Treatment. Mol Cancer Ther. 2023: 22(12_suppl):Abstract PR014. doi: 10.1158/1535-7163.TARG-23-PR014. 16. Jiang J, Jiang L, Maldonato BJ, et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers. Cancer Discov. 2024;14(6):994-1013. doi:10.1158/2159-8290.CD-23-0183. 17. Schulze CJ, Seamon KJ, Zhao Y, et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science. 2023;381(6659):794-799. doi:10.1126/science.adg9652. 18. Cuevas-Navarro A, Pourfarjam Y, Hu F, et al. Pharmacological restoration of GTP hydrolysis by mutant RAS. Nature. 2025;637(8001):224-229. doi:10.1038/s41586-024-08283-2. 19. ClinicalTrials.gov identifier: NCT06445062. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT06445062. 20. ClinicalTrials.gov identifier: NCT06040541. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT06040541. 21. ClinicalTrials.gov identifier: NCT06162221. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT06162221. 22. Revolution Medicines. Pipeline. Accessed April 2, 2026. https://www.revmed.com/pipeline/. 23. ClinicalTrials.gov identifier: NCT06625320. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT06625320. 24. ClinicalTrials.gov identifier: NCT06881784. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT06881784. 25. ClinicalTrials.gov identifier: NCT05379985. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT05379985. 26. ClinicalTrials.gov identifier: NCT07491445. Accessed April 7, 2026. https://clinicaltrials.gov/study/NCT07491445. 27. ClinicalTrials.gov identifier: NCT07252232. Accessed April 7, 2026. https://clinicaltrials.gov/study/NCT07252232. 28. ClinicalTrials.gov identifier: NCT07397338. Accessed April 21, 2026. https://clinicaltrials.gov/study/NCT07397338. 29. ClinicalTrials.gov identifier: NCT06128551. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT06128551. 30. ClinicalTrials.gov identifier: NCT07349537. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT07349537. 31. Knox JE. Discovery of RMC-9805, an oral, RAS(ON) G12D-selective covalent tri-complex inhibitor. Cancer Res. 2024;84(7):ND03. 32. Cregg J, Pota K, Tomlinson ACA, et al. Discovery of elironrasib (RMC-6291), a potent and orally bioavailable, RAS(ON) G12C-selective, covalent tri-complex inhibitor for the treatment of patients with RAS G12C-addicted cancers. J Med Chem. 2025;68:6041-6063. 33. ClinicalTrials.gov identifier: NCT05462717. Accessed April 2, 2026. https://clinicaltrials.gov/study/NCT05462717. 34. Edwards A. Discovery of RMC-5127, an oral, RAS(ON), G12V-selective, noncovalent, tri-complex inhibitor. Presented at: American Association for Cancer Research (AACR) Annual Meeting; April 25-30, 2025; Chicago, Illinois.
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