Inflammation, Epithelial to Mesenchymal Transition, and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Kostyantyn Krysan, PhD,

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Inflammation, Epithelial to Mesenchymal Transition, and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Kostyantyn Krysan, PhD, Jay M. Lee, MD, Mariam Dohadwala, PhD, Brian K. Gardner, PhD, Karen L. Reckamp, MD, Edward Garon, MD, Maie St. John, MD, Sherven Sharma, PhD, Steven M. Dubinett, MD Journal of Thoracic Oncology Volume 3, Issue 2, Pages 107-110 (February 2008) DOI: 10.1097/JTO.0b013e3181630ece Copyright © 2008 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Mechanisms of EGFR-dependent and independent MAPK/Erk pathway activation by PGE2. Epidermal growth factor receptor (EGFR) belongs to the tyrosine kinase receptors family and is a major regulator of epithelial cell growth and proliferation. It also plays an important role in tumorigenesis by promoting cancer cell proliferation, invasion, and metastasis. The MAPK/Erk signaling module is located downstream of EGFR and is a critical effector of mitogenic signaling. PGE2 is a major COX-2 metabolite abundantly present in the cancer microenvironment that exerts its effects through four G-protein coupled receptors designated as EP1, EP2, EP3, and EP4 (area 1). PGE2 signaling can promote cell proliferation, migration, and EMT by directly activating intracellular mitogenic pathways or by stimulating proteolytic release of extracellular growth factor receptor ligands that activate the mitogenic cell-surface receptors. In NSCLC, PGE2-induced MAPK/Erk activation occurs by the intracellular pathway and is therefore EGFR-independent, encouraging resistance to EGFR TKI (area 2). In contrast, in colon cancer, PGE2 can induce EGFR ligand release, activating the receptor to increase MAPK/Erk signaling through a mechanism that is sensitive to EGFR inhibition (area 3). Here the scissors indicate MMP-induced release of cell membrane-bound EGFR ligands that can occur in colon cancer. Inhibition of COX-2 abrogates both EGFR-dependent and independent PGE2-induced MAPK/Erk activation in NSCLC (area 1). COX-2: cyclooxygenase-2 (selectively inhibited by COX-2 inhibitors such as celecoxib); PGE2: prostaglandin E2; EP: E-prostanoid receptors; α, β, and γ, G-proteins: components of the G-protein coupled receptors; EGFR, epidermal growth factor receptor (P indicates tyrosines phosphorylated upon receptor activation; this process is blocked by tyrosine kinase inhibitors such as erlotinib); Ras: Ras small guanosine triphosphatase; Raf: Raf serine/threonine kinase; MEK: MAPK/Erk kinase; Erk: extracellular signal-regulated kinase; PKC: protein kinase C; MMP: matrix metalloproteinase; EMT: epithelial to mesenchymal transition. Journal of Thoracic Oncology 2008 3, 107-110DOI: (10.1097/JTO.0b013e3181630ece) Copyright © 2008 International Association for the Study of Lung Cancer Terms and Conditions