Lung Cancer Mechanisms Under Investigation
KRAS G12C Mutation
Mutations in the Kirsten rat sarcoma viral oncogene, or KRAS, are among the most common mutations in lung adenocarcimas.1 KRAS normally cycles between inactive and active forms, with activation being mediated by src homology region 2 containing phosphatase-2, or SHP2.2,3 In cancer cells, the KRAS G12C mutation has been demonstrated in vitro to shift the equilibrium towards the active form, amplifying cellular proliferation signals.4
The mesenchymal–epithelial transition oncogene, or MET, signaling pathway is normally involved in regulating cell growth, differentiation, motility, proliferation, survival, and transformation.5 In cancer, dysregulated MET signaling has been shown to activate numerous oncogenic signaling pathways, including RAC/RHO, RAS/MAPK, PI3K/AKT and STAT3/5.6-8 This oncogenic signaling may lead to neoplastic transformation due to MET’s growth-promoting activity, enhancement of cell motility, and protection from apoptosis.5,9,10
Acronyms: AKT = akt kinase; ERK = extracellular signal-regulated kinase; HGF = hepatocyte growth factor; KRAS G12C = G12C mutation in KRAS; MAPK = mitogen-activated protein kinase; MEK = mitogen-activated extracellular signal-regulated kinase; PI3K = phosphatidylinositol 3-kinase; RAC = ras-related C3 botulinum toxin substrate; RAF = rapidly accelerated fibrosarcoma; RAS = rat sarcoma viral oncogene; RHO = Rho GTPase; RTK = receptor tyrosine kinase; STAT = signal transducer and activator of transcription.
References: 1. Ding L, et al. Nature. 2008;455(7216):1069-1075. 2. Nadal E, et al. J Thorac Oncol. 2014;9(10):1513-1522. 3. Noguchi T, et al. Mol Cell Biol. 1994;14 4. Lito P, et al. Science. 2016;351(6273):604-608. 5. Benvenuti S, Milan M, Comoglio PM. In: Janetka JW, Benson RM, eds. Extracellular Targeting of Cell Signaling in Cancer: Strategies Directed at MET and RON Receptor Tyrosine Kinase Pathways. Chichester, UK: John Wiley & Sons, Ltd; 2018:43-67. 6. Gentile A, et al. Oncogene. 2008;27:5590-5598. 7. Yu J, et al. Biochem Pharmacol. 2022;195:114864. 8. Liu X, et al. Clin Cancer Res. 2011;17(22):7127-7138. 9. Grant DS, et al. Proc Natl Acad Sci USA. 1993;90(5):1937-1941. 10. Ding S, et al. Blood. 2003;101(12):4816-4822.