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

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 12.1,3,4 This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis.5

Learn more about modalities targeting KRASG12C:
small molecules.

MCL video

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 survival1,5-8

Illustration of wild type KRAS in a normal cell

Drawings are not to scale and proteins are enlarged and separated for clarity.

CLICK to learn more about GTP/GDP cycling in wild-type KRAS
Illustration of mutant KRAS in a tumor cell

Drawings are not to scale and proteins are enlarged and separated for clarity.

CLICK to learn more about GTP/GDP cycling in mutant KRASG12C

Targeting a unique surface groove9 on KRASG12C

  • Previous inhibitors were limited by non-selective binding to both mutant and wild-type KRAS1,5
  • Advances in understanding the protein structure of KRAS have revealed that the mutant cysteine of KRASG12C is located adjacent to a narrow pocket in the inactive GDP-bound form.9,10 This proximity offers the opportunity to selectively target the mutant cysteine with a covalent small molecule.11 In addition, a newly discovered groove at histidine 95 (H95) offers an additional site to stabilize binding of an inhibitor.12 Utilizing these enhanced binding interactions adjacent to the mutant cysteine, it is hypothesized that a covalent inhibitor could specifically lock KRASG12C in the inactive state, blocking oncogenic signaling without affecting wild-type signaling11,12

KRAS G12C is an important investigational target, as 13% (1 in 8) of patients with NSCLC have the KRAS G12C mutation.13

Learn more about how Amgen14 is targeting KRASG12C:
Clinical trials are underway in14:

Amgen is committed to helping patients with NSCLC and other solid tumors with KRAS G12C mutations

AKT, protein kinase B; EGFR: epidermal growth factor receptor; ERK: extracellular-signal-regulated kinase; GDP: guanosine diphosphate; GTP, guanosine 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; 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. Biernacka A, Tsongalis PD, Peterson JD, et al. Cancer Genet. 2016;209(5):195-198. 4. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Pathol Res Pract. 2009;205:858-862. 5. Ryan MB, Corcoran RB. Nat Rev Clin Oncol. 2018;15(11):709-720. 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. Ostrem JML, Shokat KM. Nat Rev Drug Discov. 2016;15(11):771-785. 12. Canon J, Rex K, Saiki AY, et al. Nature. 2019;575(7781):217-223. 13. Data on file, Amgen; 2020. 14. Q2 2019 pipeline, Amgen. Accessed October 15, 2019.