The RAS proteins (HRAS, NRAS and KRAS) are small membrane-localised G protein-like molecules of 21 kd. They act as an on/off switch linking receptor and non-receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch.

The RAS proto-oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP-hydrolysing ability of the proteins causing constitutive activation [5], which leads to increased cell proliferation and decreased apoptosis [10]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [1].

* Key recommended reading is highlighted with an asterisk

* Chen H, Smaill JB, Liu T, Ding K, Lu X. (2020) Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics. J Med Chem, 63 (23): 14404-14424. [PMID:33225706]

* Dorard C, Vucak G, Baccarini M. (2017) Deciphering the RAS/ERK pathway in vivo. Biochem Soc Trans, 45 (1): 27-36. [PMID:28202657]

* Kattan WE, Hancock JF. (2020) RAS Function in cancer cells: translating membrane biology and biochemistry into new therapeutics. Biochem J, 477 (15): 2893-2919. [PMID:32797215]

* Keeton AB, Salter EA, Piazza GA. (2017) The RAS-Effector Interaction as a Drug Target. Cancer Res, 77 (2): 221-226. [PMID:28062402]

Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, Zhang J. (2016) Ras Conformational Ensembles, Allostery, and Signaling. Chem Rev, 116 (11): 6607-65. [PMID:26815308]

Ostrem JM, Shokat KM. (2016) Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov, 15 (11): 771-785. [PMID:27469033]

* Papke B, Der CJ. (2017) Drugging RAS: Know the enemy. Science, 355 (6330): 1158-1163. [PMID:28302824]

* Quah SY, Tan MS, Teh YH, Stanslas J. (2016) Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs. Pharmacol Ther, 162: 35-57. [PMID:27016467]

* Simanshu DK, Nissley DV, McCormick F. (2017) RAS Proteins and Their Regulators in Human Disease. Cell, 170 (1): 17-33. [PMID:28666118]

1. Baines AT, Xu D, Der CJ. (2011) Inhibition of Ras for cancer treatment: the search continues. Future Med Chem, 3 (14): 1787-808. [PMID:22004085]

2. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G et al.. (2020) Discovery of a Covalent Inhibitor of KRAS^G12C (AMG 510) for the Treatment of Solid Tumors. J Med Chem, 63 (1): 52-65. [PMID:31820981]

3. Li Q, Xie K, Lin B, Gong Y. (2025) TBC1D24 promotes the progression of the breast cancer cells via ARF6/PLD axis under hypoxia. Sci Prog, 108 (3): 368504251367649. [PMID:40790967]

4. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L, Prioli N et al.. (1998) Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res, 58 (21): 4947-56. [PMID:9810004]

5. Stanley LA. (1995) Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology, 96 (3): 173-94. [PMID:7900159]

6. Xu H, Chen D, Lu J, Zhong L, Wang L, Ge J. (2025) ARF6 Promotes AML Progression via Activation of PI3K/AKT/mTOR Signaling. Cancer Med, 14 (9): e70872. [PMID:40275490]

7. Yang Y, Qing L, You C, Li Q, Xu W, Dong Z. (2025) Methuosis key gene ARF6 as a diagnostic, prognostic and immunotherapeutic marker for prostate cancer: based on a comprehensive pan-cancer multi-omics analysis. Discov Oncol, 16 (1): 882. [PMID:40410613]

8. Yoo JH, Shi DS, Grossmann AH, Sorensen LK, Tong Z, Mleynek TM, Rogers A, Zhu W, Richards JR, Winter JM et al.. (2016) ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell, 29 (6): 889-904. [PMID:27265506]

9. Zhang C, Liu Y, Yuan X, Yang X, Yang B, Huang Y, Wang F, He Z, Li Y. (2025) Identification and validation of ARF6 for a potential prognostic biomarker of acute myeloid leukemia. Cancer Cell Int, 25 (1): 218. [PMID:40542378]

10. Zhang J, Lodish HF. (2007) Endogenous K-ras signaling in erythroid differentiation. Cell Cycle, 6 (16): 1970-3. [PMID:17721087]

11. Zhao HG, Cruz-Rodriguez N, Johnson KC, Pomicter AD, Bates B, Bateman B, Haferlach T, Gu T, Ahmann J, Yan D et al.. (2025) The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia. Haematologica, [Epub ahead of print]. [PMID:40637748]