Resistance to anti-VEGF therapy mediated by autocrine IL6/STAT3 signaling and overcome by IL6 blockade

Cancer Research

Volumn 76, Issue 8, 2016, Pages 2327-2339

  Eichten, Alexandra ^a   Su, Jia ^a   Adler, Alexander P ^a   Zhang, Li ^a   Ioffe, Ella ^a   Parveen, Asma A ^a   Yancopoulos, George D ^a   Rudge, John ^a   Lowy, Israel ^a   Lin, Hsin Chieh ^a   MacDonald, Douglas ^a   Daly, Christopher ^a   Duan, Xunbao ^a   Thurston, Gavin ^a  

^a REGENERON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AFLIBERCEPT; BIOLOGICAL MARKER; CETUXIMAB; DOXORUBICIN; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; SARILUMAB; STAT3 PROTEIN; TOPOTECAN; HYBRID PROTEIN; STAT3 PROTEIN, HUMAN; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOCRINE EFFECT; CANCER CELL LINE; CANCER CHEMOTHERAPY; CANCER RESISTANCE; CANCER SURVIVAL; CONTROLLED STUDY; CYTOKINE RELEASE; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG RESPONSE; DRUG TARGETING; HUMAN; HUMAN CELL; MAJOR CLINICAL STUDY; MOUSE; MULTICENTER STUDY; NONHUMAN; OVARY CANCER; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RANDOMIZED CONTROLLED TRIAL; RECEPTOR BLOCKING; SIGNAL TRANSDUCTION; SQUAMOUS CELL CARCINOMA; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG RESISTANCE; METABOLISM; TUMOR CELL LINE; XENOGRAFT;

ANIMALS; CELL LINE, TUMOR; DRUG RESISTANCE, NEOPLASM; HETEROGRAFTS; HUMANS; INTERLEUKIN-6; MICE; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; RECOMBINANT FUSION PROTEINS; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84970952038     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-15-1443     Document Type: Article

References (46)

1. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438:967-74.
2. Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012;15:171-85.
3. Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med 2003;3:643-51.
4. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGFTrap: a VEGF blockerwith potent antitumor effects. Proc Natl Acad SciUS A 2002;99:11393-8.
5. Rudge JS, Thurston G, Davis S, Papadopoulos N, Gale N, Wiegand SJ, et al. VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGene- based discovery of the next generation of angiogenesis targets. Cold Spring Harb Symp Quant Biol 2005;70:411-8.
6. Rudge JS, Holash J, HyltonD, Russell M, Jiang S, Leidich R, et al. VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A 2007;104:18363-70.
7. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T,Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.
8. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44.
9. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:3499-506.
10. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-35.
11. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384: 665-73.
12. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592-603.
13. Loges S, Schmidt T, Carmeliet P. Mechanisms of resistance to anti-angi genic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer 2010;1:12-25.
14. Smith NR, Baker D, Farren M, Pommier A, Swann R, Wang X, et al. Tumor stromal architecture can define the intrinsic tumor response to VEGFtargeted therapy. Clin Cancer Res 2013;19:6943-56.
15. Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001;61:5090-101.
16. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009;9:798-809.
17. Song L, Turkson J, Karras JG, Jove R, Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human nonsmall cell carcinoma cells. Oncogene 2003;22:4150-65.
18. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences inMyD88-dependent IL-6 production. Science 2007;317:121-4.
19. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009;15:103-13.
20. Wei ZW, Xia GK, Wu Y, Chen W, Xiang Z, Schwarz RE, et al. CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer. Cancer Lett 2015;359: 335-43.
21. Hagihara K, Nishikawa T, Isobe T, Song J, Sugamata Y, Yoshizaki K. IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoformreal-time quantitative RT-PCR assay system. Biochem Biophys Res Commun 2004;314:363-9.
22. Hagihara K, Nishikawa T, Sugamata Y, Song J, Isobe T, Taga T, et al. Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression. Genes Cells 2005;10:1051-63.
23. West NR, Watson PH. S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer. Oncogene 2010;29:2083-92.
24. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 2009;28:2940-7.
25. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, et al. Sarilumab, a fully humanmonoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RAMOBILITY Part A trial. Ann Rheum Dis 2014;73:1626-34.
26. Tew WP, Colombo N, Ray-Coquard I, Del Campo JM, Oza A, Pereira D, et al. Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallelarm study. Cancer 2014;120:335-43.
27. Chiu CP, Moulds C, Coffman RL, Rennick D, Lee F. Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells. Proc Natl Acad Sci U S A 1988;85:7099-103.
28. Duffy SA, Taylor JM, Terrell JE, IslamM, Li Y, Fowler KE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 2008;113:750-7.
29. Liao WC, Lin JT,WuCY, Huang SP, Lin MT,WuAS, et al. Serum interleukin- 6 level but not genotype predicts survival after resection in stages II and III gastric carcinoma. Clin Cancer Res 2008;14:428-34.
30. Michalaki V, Syrigos K, Charles P, Waxman J. Serum levels of IL-6 and TNFalpha correlate with clinicopathological features and patient survival in patients with prostate cancer. Br J Cancer 2004;90:2312-6.
31. Negrier S, Perol D, Menetrier-Caux C, Escudier B, Pallardy M, Ravaud A, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6-from the Groupe Francais d'Immunotherapie. J Clin Oncol 2004;22:2371-8.
32. Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 1999;19:1427-32.
33. Scambia G, Testa U, Benedetti Panici P, Foti E, Martucci R, Gadducci A, et al. Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer 1995;71:354-6.
34. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009;15:91-102.
35. Yin W, Cheepala S, Roberts JN, Syson-Chan K, DiGiovanni J, Clifford JL. Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions. Mol Cancer 2006;5:15.
36. Selvendiran K, Bratasz A, Kuppusamy ML, Tazi MF, Rivera BK, Kuppusamy P. Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3. Int J Cancer 2009;125: 2198-204.
37. Hong DS, Angelo LS, Kurzrock R. Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 2007;110: 1911-28.
38. Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol 2012;30:1005-14.
39. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988;332:83-5.
40. Giri D, Ozen M, Ittmann M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol 2001;159:2159-65.
41. Gao SP,Mark KG, Leslie K, PaoW, Motoi N, Gerald WL, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007;117:3846-56.
42. Hartman ZC, PoageGM, den Hollander P, Tsimelzon A,Hill J, Panupinthu N, et al.Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res 2013;73:3470-80.
43. Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 2008;118:3367-77.
44. Abajo A, Boni V, Lopez I, Gonzalez-Huarriz M, Bitarte N, Rodriguez J, et al. Identification of predictive circulating biomarkers of bevacizumab-containing regimen efficacy in pre-treated metastatic colorectal cancer patients. Br J Cancer 2012;107:287-90.
45. Liu Y, Starr MD, Bulusu A, Pang H, Wong NS, Honeycutt W, et al. Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab. Cancer Med 2013;2:234-42.
46. BoigeV,Malka D,BourredjemA,DromainC,Baey C, Jacques N,et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist 2012;17:1063-72.