KRAS is the most frequently mutated oncogene
KRAS, a member of the RAS family, is a key regulator of signaling pathways responsible for cell proliferation, differentiation, and survival.1,2 KRAS is the most frequently mutated oncogene in human cancer and mutations in KRAS can result in continuous cellular proliferation and cancer development.1,2 Despite almost four decades of research, efforts to target KRAS have been unsuccessful.3
KRAS G12C is an oncogenic driver mutation
The KRAS G12C mutation occurs in about 13% of NSCLC patients, and 1%-3% of colorectal and other solid tumors. G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12.1,4,5 This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis.3
Watch this video to learn more about the mechanism of disease for KRASG12C mutated cancers
Search our clinical trials.
Visit our resources section for additional information on potential oncogenic targets.
Mutant KRASG12C supports cancer cell growth and survival1,3,6-8
Targeting a unique surface groove on KRASG12C 9
Despite decades of research, KRAS has not been successfully targeted for several reasons:
- A lack of surface targets on KRAS for binding1
- KRAS has a high affinity for GTP, resulting in ineffective competitive inhibition1,3
- Previous inhibitors were limited by non-selective binding to both mutant and wild-type KRAS3
Scientific advancements have revealed that the mutant cysteine of KRASG12C is located adjacent to a narrow pocket in the inactive GDP-bound form, making it susceptible to targeting. In addition, it is hypothesized that an adjacent histidine 95 (H95) residue may provide a site to stabilize drug-protein interactions.9,10 By utilizing this binding pocket and H95, covalent inhibitors could lock KRASG12C in the inactive state, blocking oncogenic signaling without impacting wild-type signaling.3,9
Advances in understanding the protein structure of KRAS have prompted further investigations and may provide insights into the role of KRAS mutations in cancer development and tumorigenesis.9
Learn more about how Amgen is targeting KRASG12C 11:
Amgen is committed to helping patients with NSCLC and other solid tumors with KRAS G12C mutations
ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; ERK: extracellular-signal-regulated kinase; GDP: guanosine diphosphate; GTP: guanosine-5'-triphosphate; KRAS: Kirsten rat sarcoma; MEK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; NF- κB: nuclear factor kappa-light chain enhancer of activated B cells; NSCLC: non-small cell lung cancer; PI3K: phosphatidylinositol 3-kinase; RAF: rapidly accelerated fibrosarcoma; RAL: ras-like; RAS: rat sarcoma; ROS1: c-ros oncogene 1; RTK: receptor tyrosine kinase.
1. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Nat Rev Drug Discov. 2014;13(11):828-851. 2. Downward J. Nat Rev Cancer. 2003;3(1):11-22. 3. Ryan MB, Corcoran RB. Nat Rev Clin Oncol. 2018;15(11):709-720. 4. Biernacka A, Tsongalis PD, Peterson JD, et al. Cancer Genet. 2016;209(5):195-198. 5. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Pathol Res Pract. 2009;205:858-862. 6. Simanshu DK, Nissley DV, McCormick F. Cell. 2017;170(1):17-33. 7. Neel NF, Martin TD, Stratford JK, Zand TP, Reiner DJ, Der CJ. Genes Cancer. 2011;2(3):275-287. 8. Ahmadzada T, Kao S, Reid G, Boyer M, Mahar A, Cooper WA. J Clin Med. 2018;7(6):E153. doi: 10.3390/jcm7060153. 9. Lanman BA, Chen JJ, Liu L, et al. Cancer Res. 2019;79(suppl 13):abstract 4455. 10. Saiki AY, Gaida K, Rex K, et al. Cancer Res. 2019;79(suppl 13):abstract 4484. 11. Q2 2019 pipeline, Amgen. https://www.amgenpipeline.com/~/media/amgen/full/www-amgenpipeline-com/charts/amgen-pipeline-chart.ashx. Accessed October 15, 2019.