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Olga C. J. Schuurbiers, MD, Johannes H. A. M

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1 The PI3-K/AKT-Pathway and Radiation Resistance Mechanisms in Non-small Cell Lung Cancer 
Olga C.J. Schuurbiers, MD, Johannes H.A.M. Kaanders, MD, PhD, Henricus F.M. van der Heijden, MD, PhD, Richard P.N. Dekhuijzen, MD, PhD, Wim J.G. Oyen, MD, PhD, Johan Bussink, MD, PhD  Journal of Thoracic Oncology  Volume 4, Issue 6, Pages (June 2009) DOI: /JTO.0b013e3181a1084f Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 The phosphatidylinositol-3-kinase/protein-kinase B (PI3-K/AKT) pathway and other major downstream targets of the ErbB tyrosine-kinase receptor. TK, tyrosine kinase; PI3-K, phosphatidylinositol-3-kinase; AKT, protein-kinase B; PTEN, phosphatase and TENsin homologue; mTOR, mammalian target of rapamycine; MAPK, mitogen-activated protein kinase. Journal of Thoracic Oncology 2009 4, DOI: ( /JTO.0b013e3181a1084f) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 A mouse adenocarcinoma treated with radiotherapy. A, control; B, 0.5 Gy; C, 1 Gy; D, 2 Gy. Mouse adenocarcinoma treated with radiotherapy. Hypoxic areas are green (pimidazole). DNA double strand breaks are visualized after immunohistochemical staining of γH2AX. Nuclei are blue (Hoechst 33342). A dose dependent increase in γH2AX-foci is observed with more double strand breaks in normoxic tumor areas, indicating increased radioresistance of hypoxic tumor cells. Journal of Thoracic Oncology 2009 4, DOI: ( /JTO.0b013e3181a1084f) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Fluorescent microscopic images of an undifferentiated non-small cell lung tumor (fine needle biopsy). (A) extensive areas of the endogenous hypoxia-related marker CA-9 (red/purple) indicates the presence of potentially radioresistant hypoxic tumor cells. Tumor nuclei are blue (Hoechst 33342), magnification ×20. (B) phosphorylated, activated, AKT-expression (pAKT, green), and EGFR-expression (red) relative to tumor nuclei (blue). Mismatch of epidermal growth factor receptor (EGFR) and activated protein kinase B (pAKT) illustrating the fact that the PI3-K/AKT-signaling pathway can be activated independent of the EGFR (magnification ×40). Journal of Thoracic Oncology 2009 4, DOI: ( /JTO.0b013e3181a1084f) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

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