Inhibition of PI3K by PX-866 Prevents Transforming Growth Factor-alpha-induced Pulmonary Fibrosis

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2010 Jan 1

PMID 20042669

Citations 39

Authors

Timothy D Le Cras

Thomas R Korfhagen

Cynthia Davidson

Stephanie Schmidt

Matthew Fenchel

Machiko Ikegami

Jeffrey A Whitsett

William D Hardie

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor-alpha (TGFalpha) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3'-kinase (PI3K). We previously showed that induction of lung-specific TGFalpha expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFalpha expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFalpha induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFalpha prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy.

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References

Hardie W, Korfhagen T, Sartor M, Prestridge A, Medvedovic M, Le Cras T . Genomic profile of matrix and vasculature remodeling in TGF-alpha induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2007; 37(3):309-21. PMC: 1994231. DOI: 10.1165/rcmb.2006-0455OC. View

Sawyers C . Will kinase inhibitors have a dark side?. N Engl J Med. 2006; 355(3):313-5. DOI: 10.1056/NEJMcibr062354. View

Hardie W, Dunlavy M, Ikegami M, Korfhagen T . Dose-dependent lung remodeling in transgenic mice expressing transforming growth factor-alpha. Am J Physiol Lung Cell Mol Physiol. 2001; 281(5):L1088-94. DOI: 10.1152/ajplung.2001.281.5.L1088. View

Cantley L . The phosphoinositide 3-kinase pathway. Science. 2002; 296(5573):1655-7. DOI: 10.1126/science.296.5573.1655. View

Schuessler T, Bates J . A computer-controlled research ventilator for small animals: design and evaluation. IEEE Trans Biomed Eng. 1995; 42(9):860-6. DOI: 10.1109/10.412653. View

White E, Thannickal V, Carskadon S, Dickie E, Livant D, Markwart S . Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10. Am J Respir Crit Care Med. 2003; 168(4):436-42. PMC: 1997294. DOI: 10.1164/rccm.200301-041OC. View

Ihle N, Paine-Murrieta G, Berggren M, Baker A, Tate W, Wipf P . The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther. 2005; 4(9):1349-57. PMC: 1432090. DOI: 10.1158/1535-7163.MCT-05-0149. View

Downward J . Targeting RAS and PI3K in lung cancer. Nat Med. 2008; 14(12):1315-6. DOI: 10.1038/nm1208-1315. View

Lemjabbar H, Li D, Gallup M, Sidhu S, Drori E, Basbaum C . Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J Biol Chem. 2003; 278(28):26202-7. DOI: 10.1074/jbc.M207018200. View

10.

Engelman J, Chen L, Tan X, Crosby K, Guimaraes A, Upadhyay R . Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008; 14(12):1351-6. PMC: 2683415. DOI: 10.1038/nm.1890. View

11.

Hardie W, Le Cras T, Jiang K, Tichelaar J, Azhar M, Korfhagen T . Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2003; 286(4):L741-9. DOI: 10.1152/ajplung.00208.2003. View

12.

Rice A, Moomaw C, Morgan D, Bonner J . Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol. 1999; 155(1):213-21. PMC: 1866660. DOI: 10.1016/S0002-9440(10)65115-2. View

13.

Jorissen R, Walker F, Pouliot N, Garrett T, Ward C, Burgess A . Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003; 284(1):31-53. DOI: 10.1016/s0014-4827(02)00098-8. View

14.

Dammann C, Nielsen H, Carraway 3rd K . Role of neuregulin-1 beta in the developing lung. Am J Respir Crit Care Med. 2003; 167(12):1711-6. DOI: 10.1164/rccm.200205-468OC. View

15.

Vermeer P, Einwalter L, Moninger T, Rokhlina T, Kern J, Zabner J . Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature. 2003; 422(6929):322-6. DOI: 10.1038/nature01440. View

16.

Dave V, Wert S, Tanner T, Thitoff A, Loudy D, Whitsett J . Conditional deletion of Pten causes bronchiolar hyperplasia. Am J Respir Cell Mol Biol. 2007; 38(3):337-45. PMC: 2258453. DOI: 10.1165/rcmb.2007-0182OC. View

17.

White E, Atrasz R, Hu B, Phan S, Stambolic V, Mak T . Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10). Am J Respir Crit Care Med. 2005; 173(1):112-21. PMC: 1434700. DOI: 10.1164/rccm.200507-1058OC. View

18.

Kang H, Lee C, Homer R, Elias J . Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis. J Exp Med. 2007; 204(5):1083-93. PMC: 2118575. DOI: 10.1084/jem.20061273. View

19.

Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J . Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med. 2008; 205(7):1659-72. PMC: 2442643. DOI: 10.1084/jem.20080001. View

20.

Hardie W, Davidson C, Ikegami M, Leikauf G, Le Cras T, Prestridge A . EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-alpha-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008; 294(6):L1217-25. DOI: 10.1152/ajplung.00020.2008. View