Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma

Abstract

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.

    Article  Google Scholar 

  2. Patel JD, Krilov L, Adams S, Aghajanian C, Basch E, Brose MS et al. Clinical cancer advances 2013: annual report on progress against cancer from the american society of clinical oncology. J Clin Oncol 2014; 32: 129–160.

    Article  CAS  Google Scholar 

  3. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11: 21–28.

    Article  CAS  Google Scholar 

  4. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 2013; 14: 257–264.

    Article  CAS  Google Scholar 

  5. Leon X, Hitt R, Constenla M, Rocca A, Stupp R, Kovács AF et al. A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy. Clin Oncol 2005; 17: 418–424.

    Article  CAS  Google Scholar 

  6. Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J . Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer 2008; 112: 2710–2719.

    Article  CAS  Google Scholar 

  7. Engelman JA . Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9: 550–562.

    Article  CAS  Google Scholar 

  8. Liu P, Cheng H, Roberts TM, Zhao JJ . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627–644.

    Article  CAS  Google Scholar 

  9. Du L, Shen J, Weems A, Lu SL . Role of phosphatidylinositol-3-kinase pathway in head and neck squamous cell carcinoma. J Oncol 2012; 2012: 450179.

    Article  Google Scholar 

  10. Giudice FS, Squarize CH . The determinants of head and neck cancer: unmasking the PI3K pathway mutations. J Carcinog Mutagen 2013; 2: 5.

    Google Scholar 

  11. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157–1160.

    Article  CAS  Google Scholar 

  12. Von Hoff DD, LoRusso P, Tibes R et al. A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. J Clin Oncol 2010; 28:(abstract 2541.)

  13. Munster PN, van der Noll R, Voest EE et al. Phase I first-in-human study of the PI3 kinase inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors (study P3K112826). J Clin Oncol 2011; 29: (abstract 3018.)

    Article  Google Scholar 

  14. Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012; 18: 4173–4182.

    Article  CAS  Google Scholar 

  15. Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012; 30: 282–290.

    Article  CAS  Google Scholar 

  16. Fruman DA, Rommel C . PI3K and cancer: Lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13: 140–156.

    Article  CAS  Google Scholar 

  17. Vyse S, Howitt A, Huang PH . Exploiting Synthetic Lethality and Network Biology to Overcome EGFR Inhibitor Resistance in Lung Cancer. J Mol Biol 2017; 3: (Epub ahead of print.)

  18. Neel DS, Bivona TG . Secrets of drug resistance in NSCLC exposed by new molecular definition of EMT. Clin Cancer Res 2013; 19: 3–5.

    Article  CAS  Google Scholar 

  19. Awad MM, Shaw AT . ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol 2014; 12: 429–439.

    PubMed  PubMed Central  Google Scholar 

  20. Kim HR, Kang HN, Yun MR, Lim SM, Kim CG, Ahn MJ et alCo-clinical trials demonstrate superior efficacy with combinational approach of BKM120 and erbitux over BKM120 monotherapy in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M-SCCHN) ASCO 2015;(Abstract #11010.)

  21. Jimeno A, Bauman JE, Weissman C, Adkins D, Schnadig I, Beauregard P et al. A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral Oncol 2015; 51: 383–388.

    Article  CAS  Google Scholar 

  22. Klempner SJ, Myers AP, Cantley LC . What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. Cancer Discov 2013; 3: 1345–1354.

    Article  CAS  Google Scholar 

  23. Rosell R, Karachaliou N, Morales-Espinosa D, Costa C, Molina MA, Sansano I et al. Adaptive resistance to targeted therapies in cancer. Transl Lung Cancer Res 2013; 2: 152–159.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wei W, Shin YS, Xue M, Matsutani T, Masui K, Yang H et al. Single-cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma. Cancer Cell 2016; 29: 563–573.

    Article  CAS  Google Scholar 

  25. Fallahi-Sichani M, Becker V, Izar B, Baker GJ, Lin JR, Boswell SA et al. Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol Syst Biol 2017; 13: 905.

    Article  Google Scholar 

  26. Grana B, Burris H, Rodon J et al. Oral PI3 kinase inhibitor BKM120 monotherapy in patients (pts) with advanced solid tumors: an update on safety and efficacy. J Clin Oncol 2011; 29: (abstract 3043)

    Article  Google Scholar 

  27. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 2012; 11: 317–328.

    Article  CAS  Google Scholar 

  28. Rodon J, Braña I, Siu LL, De Jonge MJ, Homji N, Mills D et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs 2014; 32: 670–681.

    Article  CAS  Google Scholar 

  29. Brachmann SM, Kleylein-Sohn J, Gaulis S, Kauffmann A, Blommers MJ, Kazic-Legueux M et al. Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations. Mol Cancer Ther 2012; 11: 1747–1757.

    Article  CAS  Google Scholar 

  30. Ren H, Chen M, Yue P, Tao H, Owonikoko TK, Ramalingam SS et al. The combination of RAD001 and NVPBKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo. Cancer Lett 2012; 325: 139–146.

    Article  CAS  Google Scholar 

  31. Guo Y, Xu F, Lu T, Duan Z, Zhang Z . Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 2012; 38: 904–910.

    Article  CAS  Google Scholar 

  32. Nagasaki T, Hara M, Shiga K, Takeyama H . Relationship between inflammation and cancer progression: recent advances in interleukin-6 signaling and its blockage in cancer therapy. Receptors Clin Investig 2014; 1: e202.

    Google Scholar 

  33. Heo TH, Wahler J, Suh N . Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget 2016; 7: 15460–15473.

    PubMed  PubMed Central  Google Scholar 

  34. Kim SM, Kwon OJ, Hong YK, Kim JH, Solca F, Ha SJ et al. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther 2012; 11: 2254–2264.

    Article  CAS  Google Scholar 

  35. Kim HS, Kwon HJ, Jung I, Yun MR, Ahn MJ, Kang BW et al. Phase II clinical and exploratory biomarker study of dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Clin Cancer Res 2015; 21: 544–552.

    Article  CAS  Google Scholar 

  36. Henriksson M, Lüscher B . Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv Cancer Res 1996; 68: 109–182.

    Article  CAS  Google Scholar 

  37. Bhattacharya N, Roy A, Roy B, Roychoudhury S, Panda CK . MYC gene amplification reveals clinical association with head and neck squamous cell carcinoma in Indian patients. J Oral Pathol Med 2009; 38: 759–763.

    Article  CAS  Google Scholar 

  38. Shi Y, Frost P, Hoang B, Benavides A, Gera J, Lichtenstein A . IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the rna-binding protein hnRNP A1. J Biol Chem 2011; 286: 67–78.

    Article  CAS  Google Scholar 

  39. Koul D, Fu J, Shen R, LaFortune TA, Wang S, Tiao N et al. Antitumor activity of NVP-BKM120—a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res 2012; 18: 184–195.

    Article  CAS  Google Scholar 

  40. Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Braña I et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 233–245.

    Article  CAS  Google Scholar 

  41. Vansteenkiste JF, Canon JL, De Braud F, Grossi F, De Pas T, Gray JE et al. Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer (NSCLC): results from the phase II BASALT-1 study. J Thorac Oncol 2015; 10: 1319–1327.

    Article  CAS  Google Scholar 

  42. Roper J, Sinnamon MJ, Coffee EM, Belmont P, Keung L, Georgeon-Richard L et al. Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Lett 2014; 347: 204–211.

    Article  CAS  Google Scholar 

  43. Hyman DM, Snyder AE, Carvajal RD, Gerecitano JF, Voss MH, Ho AL et al. Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors. Cancer Chemother Pharmacol 2015; 75: 747–755.

    Article  CAS  Google Scholar 

  44. Massarelli E, Lin H, Ginsberg LE, Tran HT, Lee JJ, Canales JR et al. Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 2015; 26: 1476–1480.

    Article  CAS  Google Scholar 

  45. Lovly CM, Shaw AT . Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res 2014; 20: 2249–2256.

    Article  CAS  Google Scholar 

  46. Ma P, Fu Y, Chen M, Jing Y, Wu J, Li K et al. Adaptive and acquired resistance to EGFR inhibitors converge on the MAPK pathway. Theranostics 2016; 6: 1232–1243.

    Article  CAS  Google Scholar 

  47. Lito P, Rosen N, Solit DB . Tumor adaptation and resistance to RAFinhibitors. Nat Med 2013; 19: 1401–1409.

    Article  CAS  Google Scholar 

  48. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulation. Cell 2010; 2: 69–80.

    Article  Google Scholar 

  49. 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; 9: 1371–1383.

    Article  CAS  Google Scholar 

  50. Eichten A, Su J, Adler A, Zhang L, Ioffe E, Parveen AA et al. Resistance to anti-VEGF therapy mediated by autocrine IL-6/STAT3 signaling and overcome by IL-6 blockade. Cancer Res 2016; 76: 2327–2339.

    Article  CAS  Google Scholar 

  51. Miller A, Brooks GD, McLeod L, Ruwanpura S, Jenkins BJ . Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis. Oncogene 2015; 34: 1510–1519.

    Article  CAS  Google Scholar 

  52. Scherzad A, Steber M, Gehrke T, Rak K, Froelich K, Schendzielorz P et al. Human mesenchymal stem cells enhance cancer cell proliferation via IL-6 secretion and activation of ERK1/2. Int J Oncol 2015; 47: 391–397.

    Article  CAS  Google Scholar 

  53. Zhang H, Wu H, Guan J, Wang L, Ren X, Shi X, Liang Z, Liu T . Paracrine SDF-1α signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells. Oncotarget 2015; 6: 3085–3097.

    Google Scholar 

  54. Sos ML, Levin RS, Gordan JD, Oses-Prieto JA, Webber JT, Salt M, Hann B et al. Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors. Cell Rep 2014; 8: 1037–1048.

    Article  CAS  Google Scholar 

  55. Ren H, Guo H, Thakur A, Zhang S, Wang T, Liang Y et al. Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells. Oncotarget 2016; 7: 67277–67287.

    PubMed  PubMed Central  Google Scholar 

  56. Mohan S, Vander Broek R, Shah S, Eytan DF, Pierce ML, Carlson SG et al. MEK inhibitor PD-0325901 overcomes resistance to PI3K/mTOR inhibitor PF-5212384 and potentiates antitumor effects in human head and neck squamous cell carcinoma. Clin Cancer Res 2015; 21: 3946–3956.

    Article  CAS  Google Scholar 

  57. Michmerhuizen NL, Leonard E, Kulkarni A, Brenner JC . Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC. Otorhinolaryngol Head Neck Surg 2016; 1: 44–50.

    Article  Google Scholar 

  58. Yadav A, Kumar B, Datta J, Teknos TN, Kumar P . IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 2011; 9: 1658–1667.

    Article  CAS  Google Scholar 

  59. Yang L, Han S, Sun Y . An IL6-STAT3 loop mediates resistance to PI3K inhibitors by inducing epithelial-mesenchymal transition and cancer stem cell expansion in human breast cancer cells. Biochem Biophys Res Commun 2014; 453: 582–587.

    Article  CAS  Google Scholar 

  60. Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 2014; 4: 998–1013.

    Article  CAS  Google Scholar 

  61. Sun S, Liu S, Duan SZ, Zhang L, Zhou H, Hu Y, Zhou X et al. Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas. Cancer Res 2014; 74: 7546–7559.

    Article  CAS  Google Scholar 

  62. Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol 2012; 180: 599–607.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (NRF-2014R1A1A1006865 to MR Yun and 2015R1A2A1A15055817 to BC Cho).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B C Cho.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yun, M., Choi, H., Kang, H. et al. ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma. Oncogene 37, 377–388 (2018). https://doi.org/10.1038/onc.2017.339

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.339

This article is cited by

Search

Quick links