Combined Inhibition of Epidermal Growth Factor and Cyclooxygenase-2 Signaling Pathways in Non-small Cell Lung Cancer Therapy_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

DENGHan-yu ^1,2 , WANGXi ² , LIGang ^1,2 , LIUQi ² ,  LINYi-dan ¹

1. Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

LINYi-dan, Email: linyidan@scu.edu.cn

Keywords：

Non-small cell lung cancer; Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs); Cyclooxy genase-2 (COX-2); Review

DOI：

10.7507/1007-4848.20160066

Video：

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The resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been brought into focus. COX-2 signal pathway was found to be closely related to EGFR signal pathway by recent researches, and there has been a growing interest to focus the researches on whether COX-2 pathway inhibition improves the efficacy of EGFR-TKIs in treating advanced NSCLC. In this review, we will illustrate recent advances of combined inhibition of EGFR and COX-2 signal pathways in NSCLC therapy.

Citation： DENGHan-yu, WANGXi, LIGang, LIUQi, LINYi-dan. Combined Inhibition of Epidermal Growth Factor and Cyclooxygenase-2 Signaling Pathways in Non-small Cell Lung Cancer Therapy. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(3): 284-288. doi: 10.7507/1007-4848.20160066 Copy

1.	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
2.	Chen W, Zheng R, Zhang S, et al. Report of cancer incidence and mortality in China, 2010. Ann Transl Med, 2014, 2(7): 61.
3.	National Cancer Institute[Web site]. Surveillance Epidemiology and End Results Program. Available at: http://seer.cancer.gov/statfacts/html/lungb.html. Accessed: 2015-10-06.
4.	Stewart EL, Tan SZ, Liu G, et al. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res, 2015, 4(1): 67-81.
5.	Spicer JF, Rudman SM. EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol, 2010, 5(4): 245-255.
6.	Sandler AB, Dubinett SM. COX-2 inhibition and lung cancer. Semin Oncol, 2004, 31(2 Suppl 7): 45-52.
7.	Deng QF, Su B, Zhao YM, et al. Study of mechanism of reverse of COX-2 inhibitor celecoxib on acquired resistance to gefitinib in non-small cell lung cancer. Respirology, 2014, 19: 37.
8.	Richardson CM, Sharma RA, Cox G, et al. Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: Potential targets for chemoprevention and systemic therapy. Lung Cancer, 2003, 39(1): 1-13.
9.	Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer, 2001, 37(Suppl 4): S3-S8.
10.	Chiu HC, Chang TY, Huang CT, et al. EGFR and myosin Ⅱ inhibitors cooperate to suppress EGFR-T790M-mutant NSCLC cells. Molecular Oncology, 2012, 6(3): 299-310.
11.	Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol, 2003, 21(20): 3798-3807.
12.	Shiau CJ, Babwah JP, da Cunha Santos G, et al. Sample features associated with success rates in population-based EGFR mutation testing. J Thorac Oncol, 2014, 9(7): 947-956.
13.	Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10): 947-957.
14.	Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol, 2012, 13(3): 239-246.
15.	Landi L, Cappuzzo F. Experience with erlotinib in the treatment of non-small cell lung cancer. Ther Adv Respir Dis, 2015, 9(4):146-163.
16.	Sugawara S, Oizumi S, Minato K, et al. Randomized phase Ⅱ study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Ann Oncol, 2015, 26(5): 888-894.
17.	Takeuchi S, Yano S. Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: sensitivity and resistance. Respir Investig, 2014, 52(6): 348-356.
18.	Lovly CM. Combating acquired resistance to tyrosine kinase inhibi-tors in lung cancer. Am Soc Clin Oncol Educ Book, 2015, 35: e165-e173.
19.	Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov, 2012, 2(10): 922-933.
20.	Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase Ⅱ trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol, 2013, 31(32): 4105-4114.
21.	Xie S, Li Y, Li X, et al. Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib. Oncotarget, 2015, 6(11): 9206-9219.
22.	Galvani E, Sun J, Leon LG, et al. NF-kappaB drives acquired resis-tance to a novel mutant-selective EGFR inhibitor. Oncotarget, 2015, 6(40):42717-42732.
23.	Faber AC, Corcoran RB, Ebi H, et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov, 2011, 1(4): 352-365.
24.	Liu YN, Chang TH, Tsai MF, et al. IL-8 confers resistance to EGFR inhibitors by inducing stem cell properties in lung cancer. Onco-target, 2015, 6(12): 10415-10431.
25.	Abou-Issa H, Alshafie G. Celecoxib: A novel treatment for lung cancer. Expert Rev Anticancer Ther, 2004, 4(5): 725-734.
26.	Gitlitz BJ, Bernstein E, Santos ES, et al. A randomized, placebo-controlled, multicenter, biomarker-selected, phase 2 study of apricoxib in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Thorac Oncol, 2014, 9(4): 577-582.
27.	Csiki I, Johnson DH. Did targeted therapy fail cyclooxygenase too? J Clin Oncol, 2006, 24(30): 4798-4800.
28.	Wiese FW, Thompson PA, Kadlubar FF. Carcinogen substrate specificity of human COX-1 and COX-2. Carcinogenesis, 2001, 22(1): 5-10.
29.	Pold M, Zhu LX, Sharma S, et al. Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC Ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. Cancer Res, 2004, 64(5): 1853-1860.
30.	Luo H, Chen Z, Jin H, et al. Cyclooxygenase-2 up-regulates vascular endothelial growth factor via a protein kinase C pathway in non-small cell lung cancer. J Exp Clin Cancer Res, 2011, 30: 6.
31.	Dohadwala M, Yang SC, Luo J, et al. Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res, 2006, 66(10): 5338-5345.
32.	Patel S, Chiplunkar S. Role of cyclooxygenase-2 in tumor progres-sion and immune regulation in lung cancer. Indian J Biochem Biophys, 2007, 44(6): 419-428.
33.	Klenke FM, Abdollahi A, Bischof M, et al. Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo. Strahlenther Onkol, 2011, 187(1): 45-51.
34.	Zhang S, Da L, Yang X, et al. Celecoxib potentially inhibits metas-tasis of lung cancer promoted by surgery in mice, via suppression of the PGE2-modulated beta-catenin pathway. Toxicol Lett, 2014, 225(2): 201-207.
35.	Chen J, Shen P, Zhang XC, et al. Efficacy and safety profile of celecoxib for treating advanced cancers: A meta-analysis of 11 randomized clinical trials. Clin Ther, 2014, 36(8): 1253-1263.
36.	Gridelli C, Gallo C, Ceribelli A, et al. Factorial phase Ⅲ randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol, 2007, 8(6): 500-512.
37.	Liu M, Yang SC, Sharma S, et al. EGFR signaling is required for TGF-beta 1 mediated COX-2 induction in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 2007, 37(5): 578-588.
38.	Cao S, Yan Y, Zhang X, et al. EGF stimulates cyclooxygenase-2 expression through the STAT5 signaling pathway in human lung adenocarcinoma A549 cells. Inter J Oncol, 2011, 39(2): 383-391.
39.	Tuccillo C, Romano M, Troiani T, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor. Clin Cancer Res, 2005, 11(3): 1268-1276.
40.	Krysan K, Reckamp KL, Dalwadi H, et al. Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res, 2005, 65(14): 6275-6281.
41.	Chen L, He Y, Huang H, et al. Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study. Med Oncol, 2008, 25(2): 161-171.
42.	Ko JC, Wang LH, Jhan JY, et al. The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells. Lung Cancer, 2009, 65(3): 290-298.
43.	Brand TM, Iida M, Luthar N, et al. Nuclear EGFR as a molecular target in cancer. Radiother Oncol, 2013, 108(3): 370-377.
44.	Dittmann KH, Mayer C, Ohneseit PA, et al. Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism. Int J Radiat Oncol Biol Phys, 2008, 70(1): 203-212.
45.	Reckamp KL, Krysan K, Morrow JD, et al. A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin Cancer Res, 2006, 12(11 Pt 1): 3381-3388.
46.	Reckamp KL, Koczywas M, Cristea MC, et al. Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer. Cancer, 2015,121(18):3298-306.
47.	Fidler MJ, Argiris A, Patel JD, et al. The potential predictive value of cyclooxygenase-2 expression and increased risk of gastrointestinal hemorrhage in advanced non-small cell lung cancer patients treated with erlotinib and celecoxib. Clin Cancer Res, 2008, 14(7): 2088-2094.
48.	Gadgeel SM, Ruckdeschel JC, Heath EI, et al. Phase Ⅱ study of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and celecoxib, a cyclooxygenase-2(COX-2) inhibitor, in patients with platinum refractory non-small cell lung cancer (NSCLC). J Thorac Oncol, 2007, 2(4): 299-305.
49.	O'Byrne KJ, Danson S, Dunlop D, et al. Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer. J Clin Oncol, 2007, 25(22): 3266-3273.
50.	Edelman MJ, Watson D, Wang X, et al. Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203. J Clin Oncol, 2008, 26(6): 848-855.
51.	Csiki I, Morrow JD, Sandler A, et al. Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase Ⅱ trial of celecoxib and docetaxel. Clin Cancer Res, 2005, 11(18): 6634-6640.

1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
2. Chen W, Zheng R, Zhang S, et al. Report of cancer incidence and mortality in China, 2010. Ann Transl Med, 2014, 2(7): 61.
3. National Cancer Institute[Web site]. Surveillance Epidemiology and End Results Program. Available at: http://seer.cancer.gov/statfacts/html/lungb.html. Accessed: 2015-10-06.
4. Stewart EL, Tan SZ, Liu G, et al. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res, 2015, 4(1): 67-81.
5. Spicer JF, Rudman SM. EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol, 2010, 5(4): 245-255.
6. Sandler AB, Dubinett SM. COX-2 inhibition and lung cancer. Semin Oncol, 2004, 31(2 Suppl 7): 45-52.
7. Deng QF, Su B, Zhao YM, et al. Study of mechanism of reverse of COX-2 inhibitor celecoxib on acquired resistance to gefitinib in non-small cell lung cancer. Respirology, 2014, 19: 37.
8. Richardson CM, Sharma RA, Cox G, et al. Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: Potential targets for chemoprevention and systemic therapy. Lung Cancer, 2003, 39(1): 1-13.
9. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer, 2001, 37(Suppl 4): S3-S8.
10. Chiu HC, Chang TY, Huang CT, et al. EGFR and myosin Ⅱ inhibitors cooperate to suppress EGFR-T790M-mutant NSCLC cells. Molecular Oncology, 2012, 6(3): 299-310.
11. Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol, 2003, 21(20): 3798-3807.
12. Shiau CJ, Babwah JP, da Cunha Santos G, et al. Sample features associated with success rates in population-based EGFR mutation testing. J Thorac Oncol, 2014, 9(7): 947-956.
13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10): 947-957.
14. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol, 2012, 13(3): 239-246.
15. Landi L, Cappuzzo F. Experience with erlotinib in the treatment of non-small cell lung cancer. Ther Adv Respir Dis, 2015, 9(4):146-163.
16. Sugawara S, Oizumi S, Minato K, et al. Randomized phase Ⅱ study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Ann Oncol, 2015, 26(5): 888-894.
17. Takeuchi S, Yano S. Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: sensitivity and resistance. Respir Investig, 2014, 52(6): 348-356.
18. Lovly CM. Combating acquired resistance to tyrosine kinase inhibi-tors in lung cancer. Am Soc Clin Oncol Educ Book, 2015, 35: e165-e173.
19. Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov, 2012, 2(10): 922-933.
20. Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase Ⅱ trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol, 2013, 31(32): 4105-4114.
21. Xie S, Li Y, Li X, et al. Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib. Oncotarget, 2015, 6(11): 9206-9219.
22. Galvani E, Sun J, Leon LG, et al. NF-kappaB drives acquired resis-tance to a novel mutant-selective EGFR inhibitor. Oncotarget, 2015, 6(40):42717-42732.
23. Faber AC, Corcoran RB, Ebi H, et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov, 2011, 1(4): 352-365.
24. Liu YN, Chang TH, Tsai MF, et al. IL-8 confers resistance to EGFR inhibitors by inducing stem cell properties in lung cancer. Onco-target, 2015, 6(12): 10415-10431.
25. Abou-Issa H, Alshafie G. Celecoxib: A novel treatment for lung cancer. Expert Rev Anticancer Ther, 2004, 4(5): 725-734.
26. Gitlitz BJ, Bernstein E, Santos ES, et al. A randomized, placebo-controlled, multicenter, biomarker-selected, phase 2 study of apricoxib in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Thorac Oncol, 2014, 9(4): 577-582.
27. Csiki I, Johnson DH. Did targeted therapy fail cyclooxygenase too? J Clin Oncol, 2006, 24(30): 4798-4800.
28. Wiese FW, Thompson PA, Kadlubar FF. Carcinogen substrate specificity of human COX-1 and COX-2. Carcinogenesis, 2001, 22(1): 5-10.
29. Pold M, Zhu LX, Sharma S, et al. Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines ENA-78/CXC Ligand (CXCL) 5 and interleukin-8/CXCL8 in human non-small cell lung cancer. Cancer Res, 2004, 64(5): 1853-1860.
30. Luo H, Chen Z, Jin H, et al. Cyclooxygenase-2 up-regulates vascular endothelial growth factor via a protein kinase C pathway in non-small cell lung cancer. J Exp Clin Cancer Res, 2011, 30: 6.
31. Dohadwala M, Yang SC, Luo J, et al. Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res, 2006, 66(10): 5338-5345.
32. Patel S, Chiplunkar S. Role of cyclooxygenase-2 in tumor progres-sion and immune regulation in lung cancer. Indian J Biochem Biophys, 2007, 44(6): 419-428.
33. Klenke FM, Abdollahi A, Bischof M, et al. Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo. Strahlenther Onkol, 2011, 187(1): 45-51.
34. Zhang S, Da L, Yang X, et al. Celecoxib potentially inhibits metas-tasis of lung cancer promoted by surgery in mice, via suppression of the PGE2-modulated beta-catenin pathway. Toxicol Lett, 2014, 225(2): 201-207.
35. Chen J, Shen P, Zhang XC, et al. Efficacy and safety profile of celecoxib for treating advanced cancers: A meta-analysis of 11 randomized clinical trials. Clin Ther, 2014, 36(8): 1253-1263.
36. Gridelli C, Gallo C, Ceribelli A, et al. Factorial phase Ⅲ randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study. Lancet Oncol, 2007, 8(6): 500-512.
37. Liu M, Yang SC, Sharma S, et al. EGFR signaling is required for TGF-beta 1 mediated COX-2 induction in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 2007, 37(5): 578-588.
38. Cao S, Yan Y, Zhang X, et al. EGF stimulates cyclooxygenase-2 expression through the STAT5 signaling pathway in human lung adenocarcinoma A549 cells. Inter J Oncol, 2011, 39(2): 383-391.
39. Tuccillo C, Romano M, Troiani T, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor. Clin Cancer Res, 2005, 11(3): 1268-1276.
40. Krysan K, Reckamp KL, Dalwadi H, et al. Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res, 2005, 65(14): 6275-6281.
41. Chen L, He Y, Huang H, et al. Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study. Med Oncol, 2008, 25(2): 161-171.
42. Ko JC, Wang LH, Jhan JY, et al. The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells. Lung Cancer, 2009, 65(3): 290-298.
43. Brand TM, Iida M, Luthar N, et al. Nuclear EGFR as a molecular target in cancer. Radiother Oncol, 2013, 108(3): 370-377.
44. Dittmann KH, Mayer C, Ohneseit PA, et al. Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism. Int J Radiat Oncol Biol Phys, 2008, 70(1): 203-212.
45. Reckamp KL, Krysan K, Morrow JD, et al. A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin Cancer Res, 2006, 12(11 Pt 1): 3381-3388.
46. Reckamp KL, Koczywas M, Cristea MC, et al. Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer. Cancer, 2015,121(18):3298-306.
47. Fidler MJ, Argiris A, Patel JD, et al. The potential predictive value of cyclooxygenase-2 expression and increased risk of gastrointestinal hemorrhage in advanced non-small cell lung cancer patients treated with erlotinib and celecoxib. Clin Cancer Res, 2008, 14(7): 2088-2094.
48. Gadgeel SM, Ruckdeschel JC, Heath EI, et al. Phase Ⅱ study of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and celecoxib, a cyclooxygenase-2(COX-2) inhibitor, in patients with platinum refractory non-small cell lung cancer (NSCLC). J Thorac Oncol, 2007, 2(4): 299-305.
49. O'Byrne KJ, Danson S, Dunlop D, et al. Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer. J Clin Oncol, 2007, 25(22): 3266-3273.
50. Edelman MJ, Watson D, Wang X, et al. Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203. J Clin Oncol, 2008, 26(6): 848-855.
51. Csiki I, Morrow JD, Sandler A, et al. Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase Ⅱ trial of celecoxib and docetaxel. Clin Cancer Res, 2005, 11(18): 6634-6640.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Combined Inhibition of Epidermal Growth Factor and Cyclooxygenase-2 Signaling Pathways in Non-small Cell Lung Cancer Therapy

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