At Revolution Medicines, Medical Affairs supports Europe-based healthcare professionals in oncology by sharing rigorous scientific information related to RAS-driven cancers.
RAS(ON) Biology
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
Abbreviations
AKT, protein kinase B; ERK, extracellular signal-regulated kinase; GAP, GTPase-activating protein; GDP, guanosine diphosphate; GTPase, guanosine triphosphatase; GEF, guanine nucleotide exchange factor; GTP, guanosine triphosphate; HRAS, Harvey rat sarcoma viral oncogene homolog; KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NRAS, neuroblastoma rat sarcoma viral oncogene homolog; PI3K, phosphoinositide 3-kinase; 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;80(14):2969-2974. doi:10.1158/0008-5472.CAN-19-3682. 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: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. Signal Transduct Target Ther. 2023;8:455. doi: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.
If your inquiry involves an Adverse Event Report or Product Quality Complaint, please do not submit it using the Medical Information Request form. Instead, email us at medinfo-eur@revmed.com, or call us directly using the country-specific phone numbers listed below:
{{break}}
Hours of operation: Monday-Friday, 9:00 AM–5:00 PM CET
{{break}}
United Kingdom Toll-Free:
0808 271 1039
{{break}}
Spain Toll-Free:
900 752 149
{{break}}
Germany Toll-Free:
0800 1823096
{{break}}
France Toll-Free:
0 805 98 05 53
{{break}}
Italy Toll-Free:
800 787 833
{{break}}
Netherlands & Other European Countries:
+31 20 225 4454