Lung Cancer Mechanisms Under Investigation

Pro-Tumor Inflammation and the Role of IL-1β

Extensive preclinical evidence suggests that chronic inflammation can promote tumor cell growth through the production of proinflammatory cytokines, such as interleukin-1β, or IL-1β, which may promote the infiltration of immunosuppressive cells that impair the antitumor response.1,2 Preclinical evidence also suggests that IL-1β may be an important upstream driver of pro-tumor inflammation in lung cancers, such as non-small cell lung cancer.3,4

Watch the video below to learn more about the role of IL-1β in pro-tumor inflammation.

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KRAS G12C Mutation

Mutations in the Kirsten rat sarcoma viral oncogene, or KRAS, are among the most common mutations in lung adenocarcimas.5 KRAS normally cycles between inactive and active forms, with activation being mediated by src homology region 2 containing phosphatase-2, or SHP2.6,7 In cancer cells, the KRAS G12C mutation has been demonstrated in vitro to shift the equilibrium towards the active form, amplifying cellular proliferation signals.8

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MET Dysregulation

The mesenchymalepithelial transition oncogene, or MET, signaling pathway is normally involved in regulating cell growth, differentiation, motility, proliferation, survival, and transformation.9 In cancer, dysregulated MET signaling has been shown to activate numerous oncogenic signaling pathways, including RAC/RHO, RAS/MAPK, PI3K/AKT and STAT3/5.10-12 This oncogenic signaling may lead to neoplastic transformation due to MET’s growth-promoting activity, enhancement of cell motility, and protection from apoptosis.9,13,14

 

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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. Ohshima H, Miyoshi N, Tomono S. In: Hiraku Y, Kawanishi S, Ohshima H, eds. Cancer and Inflammation Mechanisms: Chemical, Biological and Clinical Aspects, First Edition. Hoboken, NJ: John Wiley and Sons, Inc; 2014:1-7. 2. Bunt SK, et al. J Immunol. 2006;176:284-290. 3. Carmi Y, et al. J Immunol. 2013;190(7):3500-3509. 4. Wang L, et al. Cancer Res. 2014;74(17):4720-4730. 5. Ding L, et al. Nature. 2008;455(7216):1069-1075. 6. Nadal E, et al. J Thorac Oncol. 2014;9(10):1513-1522. 7. Noguchi T, et al. Mol Cell Biol. 1994;14(10):6674-6682. 8. Lito P, et al. Science. 2016;351(6273):604-608. 9. 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. 10. Gentile A, et al. Oncogene. 2008;27:5590-5598. 11. Yu J, et al. Biochem Pharmacol. 2022;195:114864. 12. Liu X, et al. Clin Cancer Res. 2011;17(22):7127-7138. 13. Grant DS, et al. Proc Natl Acad Sci USA. 1993;90(5):1937-1941. 14. Ding S, et al. Blood. 2003;101(12):4816-4822.