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Targeting KRAS G12C: A Driver Mutation in Cancer

KRAS signaling in normal cells

  • The KRAS protein is a signaling GTPase that cycles between active GTP-bound and inactive GDP-bound states to regulate intracellular signaling in response to extracellular growth factors1-3
  • GTP-bound KRAS activates multiple downstream signaling pathways involved in cell proliferation, migration, and survival, including the MAPK and PI3K pathways2-4
KRAS signaling in normal cells

Mutated KRAS in cancer

  • KRAS is one of the most prevalent oncogenes in human cancers with the highest mutation rate among all cancers.1,4,6 Oncogenic mutations in the KRAS protein, such as the glycine-to-cysteine mutation at position 12 (G12C), interfere with the transition from GTP-bound to GDP-bound states2,4,5
  • Locking KRAS G12C in its constantly active state increases downstream oncogenic signaling, resulting in uncontrollable cancer cell growth and tumor formation2,4-6
  • The KRAS G12C mutation is often associated with resistance to select chemotherapies and targeted therapies1,7,9,10
Mutated KRAS in cancer
    • Uprety D, Adjei AA. KRAS: from undruggable to a druggable cancer target. Cancer Treat Rev. 2020;89:102070. PMID: 32711246

      Uprety D, Adjei AA. KRAS: from undruggable to a druggable cancer target. Cancer Treat Rev. 2020;89:102070. PMID: 32711246

    • Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533-552. PMID: 32528145

      Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533-552. PMID: 32528145

    • Khan AQ, Kuttikrishnan S, Siveen KS, et al. RAS-mediated oncogenic signaling pathways in human malignancies. Semin Cancer Biol. 2019;54:1-13. PMID: 29524560

      Khan AQ, Kuttikrishnan S, Siveen KS, et al. RAS-mediated oncogenic signaling pathways in human malignancies. Semin Cancer Biol. 2019;54:1-13. PMID: 29524560

    • Friedlaender A, Drilon A, Weiss GJ, Banna GL, Addeo A. KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85:101978. PMID: 32062493

      Friedlaender A, Drilon A, Weiss GJ, Banna GL, Addeo A. KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85:101978. PMID: 32062493

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

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

    • Román M, Baraibar I, López I, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018;17(1):33. PMID: 29455666

      Román M, Baraibar I, López I, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018;17(1):33. PMID: 29455666

    • Hartmaier RJ, Albacker LA, Chmielecki J, et al. High-throughput genomic profiling of adult solid tumors reveals novel insights into cancer pathogenesis. Cancer Res. 2017;77(9):2464-2475. PMID: 28235761

      Hartmaier RJ, Albacker LA, Chmielecki J, et al. High-throughput genomic profiling of adult solid tumors reveals novel insights into cancer pathogenesis. Cancer Res. 2017;77(9):2464-2475. PMID: 28235761

    • Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187. PMID: 33497555

      Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187. PMID: 33497555

    • Nadal E, Chen G, Prensner JR, et al. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma J. Thorac Oncol. 2014;9(10):1513-1522. PMID: 25170638

      Nadal E, Chen G, Prensner JR, et al. KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma J. Thorac Oncol. 2014;9(10):1513-1522. PMID: 25170638

    • Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923-929. PMID: 28208157

      Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923-929. PMID: 28208157

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