Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

English version

Autoři: Rachel A. O’Keefe ^aff001; Neil E. Bhola ^aff001; David S. Lee ^aff001; Daniel E. Johnson ^aff001; Jennifer R. Grandis ^aff001
Působiště autorů: Department of Otolaryngology–Head and Neck Surgery, University of California San Francisco, San Francisco, CA, United States of America ^aff001
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227261

Souhrn

The epidermal growth factor receptor inhibitor cetuximab is the only oncogene-targeted agent that has been FDA approved for the treatment of head and neck squamous cell carcinoma (HNSCC). Currently, there are no biomarkers used in the clinic to predict which HNSCC tumors will respond to cetuximab, and even in tumors that regress with treatment, acquired resistance occurs in the majority of cases. Though a number of mechanisms of acquired resistance to cetuximab have been identified in preclinical studies, no therapies targeting these resistance pathways have yet been effectively translated into the clinic. To address this unmet need, we examined the role of the cytokine interleukin 6 (IL-6) in acquired cetuximab resistance in preclinical models of HNSCC. We found that IL-6 secretion was increased in PE/CA-PJ49 cells that had acquired resistance to cetuximab compared to the parental cells from which they were derived. However, addition of exogenous IL-6 to parental cells did not promote cetuximab resistance, and inhibition of the IL-6 pathway did not restore cetuximab sensitivity in the cetuximab-resistant cells. Further examination of the IL-6 pathway revealed that expression of IL6R, which encodes a component of the IL-6 receptor, was decreased in cetuximab-resistant cells compared to parental cells, and that treatment of the cetuximab-resistant cells with exogenous IL-6 did not induce phosphorylation of signal transducer and activator of transcription 3, suggesting that the IL-6 pathway was functionally impaired in the cetuximab-resistant cells. These findings demonstrate that, even if IL-6 is increased in the context of cetuximab resistance, it is not necessarily required for maintenance of the resistant phenotype, and that targeting the IL-6 pathway may not restore sensitivity to cetuximab in cetuximab-refractory HNSCC.

Klíčová slova:

Cancer treatment – Cell staining – Crystal violet staining – Head and neck squamous cell carcinoma – RNA extraction – Secretion – Small interfering RNAs – STAT signaling

Zdroje

1. Leemans CR, Braakhuis BJM, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11(1):9–22. doi: 10.1038/nrc2982 21160525

2. Behren A, Kamenisch Y, Muehlen S, Flechtenmacher C, Haberkorn U, Hilber H, et al. Development of an oral cancer recurrence mouse model after surgical resection. Int J Oncol. 2010;36:849–55. doi: 10.3892/ijo_00000562 20198328

3. Cassell A, Freilino ML, Lee J, Barr S, Wang L, Panahandeh MC, et al. Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models. Neoplasia. 2012;14(11):1005–14. doi: 10.1593/neo.121212 23226094

4. Pollock NI, Grandis JR. HER2 as a therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res. 2014;21(3):526–33. doi: 10.1158/1078-0432.CCR-14-1432 25424855

5. Johnston PA, Sen M, Hua Y, Camarco DP, Shun TY, Lazo JS, et al. HCS campaign to identify selective inhibitors of IL-6-induced STAT3 pathway activation in head and neck cancer cell lines. Assay Drug Dev Technol. 2015;13(7):356–76. doi: 10.1089/adt.2015.663 26317883

6. Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82. doi: 10.1038/nature14129 25631445

7. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer. N Engl J Med. 2008;359(11):1116–27. doi: 10.1056/NEJMoa0802656 18784101

8. Mehra R, Cohen RB, Burtness B a. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol. 2008;6(10):742–50. 18997665

9. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus Cetuximab for Squamous- Cell Carcinoma of the Head and Neck. New Engl Jounal Med. 2006;354(6):567–78.

10. Cassell A, Grandis JR. Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. Expert Opin Investig Drugs. 2010;19(6):709–22. doi: 10.1517/13543781003769844 20415598

11. Luedke E, Jaime-Ramirez AC, Bhave N, Roda J, Choudhary MM, Kumar B, et al. Cetuximab therapy in head and neck cancer: Immune modulation with interleukin-12 and other natural killer cell-activating cytokines. Surgery. 2012;152(3):431–40. doi: 10.1016/j.surg.2012.05.035 22770960

12. Li H, Wawrose JS, Gooding WE, Garraway LA, Yan VW, Peyser ND, et al. Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: A rational approach to preclinical model selection. Mol Cancer Res. 2014;12(4):571–82. doi: 10.1158/1541-7786.MCR-13-0396 24425785

13. Chen CC, Chen WC, Lu CH, Wang WH, Lin PY, Lee K Der, et al. Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor. Int J Radiat Oncol Biol Phys. 2010;76(4):1214–24. doi: 10.1016/j.ijrobp.2009.09.059 20206020

14. Rebucci M, Peixoto P, Dewitte A, Wattez N, de Nuncques M-A, Rezvoy N, et al. Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance. Int J Oncol. 2011;38:189–200. 21109940

15. Boeckx C, Op de Beeck K, Wouters A, Deschoolmeester V, Limame R, Zwaenepoel K, et al. Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins. Cancer Lett. 2014;354(2):365–77. doi: 10.1016/j.canlet.2014.08.039 25192874

16. Chen LF, Cohen EEW, Grandis JR. New strategies in head and neck cancer: understanding resistance to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2010;16(9):2489–95. doi: 10.1158/1078-0432.CCR-09-2318 20406834

17. Stabile LP, Egloff AM, Gibson MK, Gooding WE, Ohr J, Zhou P, et al. IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer. Oral Oncol. 2017;69:38–45. doi: 10.1016/j.oraloncology.2017.03.011 28559019

18. Licitra L, Mesia R, Rivera F, Remenar E, Hitt R, Erfan J, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol. 2011;22(5):1078–87. doi: 10.1093/annonc/mdq588 21048039

19. Licitra L, Sto S, Kerr KM, Cutsem E Van, Pirker R, Hirsch FR, et al. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies. 2013;1161–8.

20. Hsu H-C, Thiam TK, Lu Y-J, Yeh CY, Tsai W-S, You JF, et al. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget. 2016;7(16):22257–70. doi: 10.18632/oncotarget.8076 26989027

21. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101(4):715–21. doi: 10.1038/sj.bjc.6605177 19603018

22. Rampias T, Giagini A, Siolos S, Matsuzaki H, Sasaki C, Scorilas A, et al. RAS/PI3K crosstalk and cetuximab resistance in head and neck squamous cell carcinoma. Clin Cancer Res. 2014;20(11):2933–46. doi: 10.1158/1078-0432.CCR-13-2721 24696319

23. Braig F, Voigtlaender M, Schieferdecker A, Busch C-J, Laban S, Grob T, et al. Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma. Oncotarget. 2015;7(28).

24. Duffy SA, Taylor JMG, Terrell JE, Islam M, Li Y, Fowler KE, et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer. 2008;113(4):750–7. doi: 10.1002/cncr.23615 18536030

25. Sen M, Joyce S, Panahandeh M, Li C, Thomas SM, Maxwell J, et al. Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. Clin Cancer Res. 2012;18(18):4986–96. doi: 10.1158/1078-0432.CCR-12-0792 22825581

26. Wang Z, Martin D, Molinolo A a, Patel V, Iglesias-Bartolome R, Sol Degese M, et al. mTOR co-targeting in cetuximab resistance in head and neck cancers harboring PIK3CA and RAS mutations. J Natl Cancer Inst. 2014;106(9):1–11.

27. Berkant Avci A, Feist E, Rüdiger Burmester G. Targeting IL-6 or IL‑6 receptor in rheumatoid arthritis: What’s the difference? BioDrugs. 2018;32(6):531–46. doi: 10.1007/s40259-018-0320-3 30488231

28. Le RQ, Li L, Yuan W, Short SS, Nie L, Habtemariam BA, et al. FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23:943–7. doi: 10.1634/theoncologist.2018-0028 29622697

29. Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res. 2014;2(4):288–94. doi: 10.1158/2326-6066.CIR-14-0022 24764575

30. Leonard B, Brand TM, O’Keefe RA, Lee ED, Zeng Y, Kemmer JD, et al. BET inhibition overcomes receptor tyrosine kinase-mediated cetuximab resistance in HNSCC. Cancer Res. 2018;78(15):4331–3. doi: 10.1158/0008-5472.CAN-18-0459 29792310

31. Gasparian A V, Burkhart C a, Purmal A a, Brodsky L, Pal M, Saranadasa M, et al. Curaxins: Anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT. Sci Transl Med. 2011;3(95):95ra74. doi: 10.1126/scitranslmed.3002530 21832239

32. De S, Lindner DJ, Coleman CJ, Wildey G, Dowlati A, Stark GR. The FACT inhibitor CBL0137 synergizes with cisplatin in small-cell lung cancer by increasing NOTCH1 expression and targeting tumor-initiating cells. 2018;78(12):2396–407.

33. Stanam A, Love-Homan L, Joseph TS, Espinosa-Cotton M, Simons AL. Upregulated interleukin-6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma. Mol Oncol. 2015;

34. Johnston PA, Grandis JR. STAT3 signaling: anticancer strategies and challenges. Mol Interv. 2011;11(1):18–26. doi: 10.1124/mi.11.1.4 21441118

35. Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res. 2003;63:2948–56. 12782602

36. Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci. 2011;122(4):143–59.

37. Sun Kim H, Chen Y-C, Nör F, Warner KA, Andrews A, Wagner VP, et al. Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels. Oncotarget. 2017;8(59):100339–52. doi: 10.18632/oncotarget.22225 29245982

38. Kline CN, Joseph NM, Grenert JP, Van Ziffle J, Talevich E, Onodera C, et al. Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro Oncol. 2017;19(5):699–709. doi: 10.1093/neuonc/now254 28453743

39. Gao J, Zhao S, Halstensen TS. Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep. 2016;35:3265–74. doi: 10.3892/or.2016.4765 27108527

40. Verboogen RJ, Revelo NH, Beest M, Bogaart G Van Den. Interleukin- 6 secretion is limited by self-signaling in endosomes. 2019;11:144–57. doi: 10.1093/jmcb/mjy038 30016456

41. Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014 Feb;26(1):38–47. doi: 10.1016/j.smim.2014.01.008 24602448

42. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809. doi: 10.1038/nrc2734 19851315

43. Blakely CM, Pazarentzos E, Olivas V, Asthana S, Yan JJ, Tan I, et al. NF-κB-Activating Complex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer. Cell Rep. 2015;11(1):98–110. doi: 10.1016/j.celrep.2015.03.012 25843712

44. Fletcher EVM, Love-Homan L, Sobhakumari A, Feddersen CR, Koch AT, Goel A, et al. EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC. Mol Cancer Res. 2013;11(12):1574–84. doi: 10.1158/1541-7786.MCR-13-0187 24048704

45. Lv D, Jia F, Hou Y, Sang Y, Alvarez AA, Zhang W, et al. Histone Acetyltransferase KAT6A Upregulates PI3K / AKT Signaling through TRIM24 Binding. 2017;77(22). doi: 10.1158/0008-5472.CAN-17-1388 29021135

46. Kennedy J, Goudie D, Blair E, Chandler K, Joss S, McKay V, et al. KAT6A Syndrome: Genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet Med. 2019;21(4):850–60. doi: 10.1038/s41436-018-0259-2 30245513

47. Bui N, Huang JK, Bojorquez-gomez A, Licon K, Sanchez KS, Tang SN, et al. Disruption of NSD1 in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation. Mol Cancer Ther. 2018;17(7):1585–95. doi: 10.1158/1535-7163.MCT-17-0937 29636367

48. Pan C, Izreig S, Yarbrough WG, Issaeva N. NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents. Cancers Head Neck. 2019;4(3):1–13.

49. Cheung LWT, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1(2):170–85. doi: 10.1158/2159-8290.CD-11-0039 21984976

50. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Arman B, et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. 2012;(May).

51. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal Complementary Data Sources and Analysis Options. Sci Signal. 2013;6(269):1–20.

52. Beck TN, Georgopoulos R, Shagisultanova EI, Sarcu D, Handorf EA, Dubyk C, et al. EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer. Mol Cancer Ther. 2016;15(10):2486–97. doi: 10.1158/1535-7163.MCT-16-0243 27507850

53. Stein-O’Brien G, Kagohara LT, Li S, Thakar M, Ranaweera R, Ozawa H, et al. Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance. Genome Med. 2018;10(1):1–22. doi: 10.1186/s13073-017-0512-3

Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

Souhrn

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