FGFR Signaling as a Target for Lung Cancer Therapy

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FGFR Signaling as a Target for Lung Cancer Therapy Arpita Desai, MD, Alex A. Adjei, MD, PhD Journal of Thoracic Oncology Volume 11, Issue 1, Pages 9-20 (January 2016) DOI: 10.1016/j.jtho.2015.08.003 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 The various fibroblast growth factor receptor splice variants and receptor activation. Alternative splicing of the Ig3-like domain is responsible for the formation of isoforms with different ligand-binding specificity. Binding of fibroblast growth factor ligands and heparin sulfate proteoglycan to the fibroblast growth factor receptor activates the receptor, which results in dimerization of the receptor–ligand complex and in turn leads to transphosphorylation of the tyrosine kinase domains, endocytosis of the complex, and ultimately, activation of downstream signaling cascades. Journal of Thoracic Oncology 2016 11, 9-20DOI: (10.1016/j.jtho.2015.08.003) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 The downstream signaling pathway after activation of ligand-dependent fibroblast growth factor receptor. Activation of fibroblast growth factor receptor facilitates the attachment of docking proteins and activation of key downstream pathways: RAS–RAF–MAPK, phosphoinositide 3-kinase (PI3K)–AKT–mTOR (mammalian target of rapamycin), phospholipase c gamma, and signal transducer and activator of transcription (STAT). The mTOR complex (mTORC) consists of mTOR, raptor, proline-rich AKT substrate 40 kDa (PRAS40), and mammalian LST8 (mLST8), which is sensitive to and responsible for rapamycin-induced processes.11 Activation of the P13K pathway by either growth factors or mutations leads to activation of AKT. AKT increases the downstream signaling of mTORC by phosphorylating TSC2 and PRAS40, thereby preventing the activity of negative regulators of mTORC.14 This mTORC activation results in the phosphorylation of 4EBP1 (eukaryotic translation initiation factor 4E–binding protein), which prevents inactivation of Eif4E (eukaryotic initiation factor 4E), thereby leading to cellular proliferation and angiogenesis through increased mRNA translation of cyclin D, Bcl-2, and VEGF.11 In addition, mTORC phosphorylates S6K1, thus leading to translation of mRNAs encoding for proteins and elongation factors. Hypoxia-mediated inhibition of mTORC1 requires expression of REDD1 (regulated in development and DNA damage responses 1) and is dependent on tuberous sclerosis complex function.15 Journal of Thoracic Oncology 2016 11, 9-20DOI: (10.1016/j.jtho.2015.08.003) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions