Skip to main content
Erschienen in: Journal of Cancer Research and Clinical Oncology 3/2012

01.03.2012 | Original Paper

Autocrine epidermal growth factor receptor ligand production and cetuximab response in head and neck squamous cell carcinoma cell lines

verfasst von: Goro Oshima, Johan Wennerberg, Takashi Yamatodani, Elisabeth Kjellén, Hiroyuki Mineta, Anders Johnsson, Lars Ekblad

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 3/2012

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Predictive strategies for the treatment efficacy of cetuximab are currently not available for head and neck cancer. We investigated the correlation between the expression of epidermal growth factor receptor (EGFR) ligands and EGFR expression, and the growth inhibitory activity of cetuximab in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines.

Methods

The growth inhibiting effect of cetuximab was measured for eight HNSCC cell lines and correlated with the autocrine production of five EGFR ligands as measured by ELISA, and the mRNA expression of two ligands, as measured by quantitative RT-PCR. EGFR expression was assessed by western blot analysis.

Results

There was a good correlation between the expression of four of the EGFR ligands (TGF-α, amphiregulin, epiregulin and epigen) and the growth inhibiting effect of cetuximab. TGF-α had the highest predictive potential but had to be combined with epigen for full prediction. EGFR expression also correlated with cetuximab sensitivity but less clearly.

Conclusions

The results indicate that the expression of several EGFR ligands has to be used to predict sensitivity to cetuximab in HNSCC. This has to be further evaluated in clinical samples.
Literatur
Zurück zum Zitat Astsaturov I, Cohen RB, Harari P (2007) EGFR-targeting monoclonal antibodies in head and neck cancer. Curr Cancer Drug Targets 7(7):650–665PubMedCrossRef Astsaturov I, Cohen RB, Harari P (2007) EGFR-targeting monoclonal antibodies in head and neck cancer. Curr Cancer Drug Targets 7(7):650–665PubMedCrossRef
Zurück zum Zitat Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S, Rowinsky EK, Xu LA, Harbison CT, Clark EA, Mauro DJ, Khambata-Ford S (2011) Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer 104(3):488–495. doi:10.1038/sj.bjc.6606054 PubMedCrossRef Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S, Rowinsky EK, Xu LA, Harbison CT, Clark EA, Mauro DJ, Khambata-Ford S (2011) Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer 104(3):488–495. doi:10.​1038/​sj.​bjc.​6606054 PubMedCrossRef
Zurück zum Zitat Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578. doi:10.1056/NEJMoa053422 PubMedCrossRef Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578. doi:10.​1056/​NEJMoa053422 PubMedCrossRef
Zurück zum Zitat Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) 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 11(1):21–28. doi:10.1016/S1470-2045(09)70311-0 PubMedCrossRef Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) 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 11(1):21–28. doi:10.​1016/​S1470-2045(09)70311-0 PubMedCrossRef
Zurück zum Zitat Chang MH, Ahn HK, Lee J, Jung CK, Choi YL, Park YH, Ahn JS, Park K, Ahn MJ (2011) Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Cancer 117(1):143–151. doi:10.1002/cncr.25560 PubMedCrossRef Chang MH, Ahn HK, Lee J, Jung CK, Choi YL, Park YH, Ahn JS, Park K, Ahn MJ (2011) Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Cancer 117(1):143–151. doi:10.​1002/​cncr.​25560 PubMedCrossRef
Zurück zum Zitat Dempsey PJ, Coffey RJ (1994) Basolateral targeting and efficient consumption of transforming growth factor-alpha when expressed in Madin-Darby canine kidney cells. J Biol Chem 269(24):16878–16889PubMed Dempsey PJ, Coffey RJ (1994) Basolateral targeting and efficient consumption of transforming growth factor-alpha when expressed in Madin-Darby canine kidney cells. J Biol Chem 269(24):16878–16889PubMed
Zurück zum Zitat Egloff AM, Grandis JR (2009) Improving response rates to EGFR-targeted therapies for head and neck squamous cell carcinoma: candidate predictive biomarkers and combination treatment with Src inhibitors. J Oncol 2009:896407. doi:10.1155/2009/896407 PubMed Egloff AM, Grandis JR (2009) Improving response rates to EGFR-targeted therapies for head and neck squamous cell carcinoma: candidate predictive biomarkers and combination treatment with Src inhibitors. J Oncol 2009:896407. doi:10.​1155/​2009/​896407 PubMed
Zurück zum Zitat Fontanini G, De Laurentiis M, Vignati S, Chine S, Lucchi M, Silvestri V, Mussi A, De Placido S, Tortora G, Bianco AR, Gullick W, Angeletti CA, Bevilacqua G, Ciardiello F (1998) Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 4(1):241–249PubMed Fontanini G, De Laurentiis M, Vignati S, Chine S, Lucchi M, Silvestri V, Mussi A, De Placido S, Tortora G, Bianco AR, Gullick W, Angeletti CA, Bevilacqua G, Ciardiello F (1998) Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 4(1):241–249PubMed
Zurück zum Zitat Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ (1998b) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90(11):824–832CrossRef Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ (1998b) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90(11):824–832CrossRef
Zurück zum Zitat Hatakeyama H, Cheng H, Wirth P, Counsell A, Marcrom SR, Wood CB, Pohlmann PR, Gilbert J, Murphy B, Yarbrough WG, Wheeler DL, Harari PM, Guo Y, Shyr Y, Slebos RJ, Chung CH (2010) Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One 5(9):e12702. doi:10.1371/journal.pone.0012702 PubMedCrossRef Hatakeyama H, Cheng H, Wirth P, Counsell A, Marcrom SR, Wood CB, Pohlmann PR, Gilbert J, Murphy B, Yarbrough WG, Wheeler DL, Harari PM, Guo Y, Shyr Y, Slebos RJ, Chung CH (2010) Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One 5(9):e12702. doi:10.​1371/​journal.​pone.​0012702 PubMedCrossRef
Zurück zum Zitat Henriksson E, Baldetorp B, Borg A, Kjellen E, Akervall J, Wennerberg J, Wahlberg P (2006) p53 mutation and cyclin D1 amplification correlate with cisplatin sensitivity in xenografted human squamous cell carcinomas from head and neck. Acta Oncol 45(3):300–305. doi:10.1080/02841860600547380 PubMedCrossRef Henriksson E, Baldetorp B, Borg A, Kjellen E, Akervall J, Wennerberg J, Wahlberg P (2006) p53 mutation and cyclin D1 amplification correlate with cisplatin sensitivity in xenografted human squamous cell carcinomas from head and neck. Acta Oncol 45(3):300–305. doi:10.​1080/​0284186060054738​0 PubMedCrossRef
Zurück zum Zitat Henriksson E, Kjellen E, Baldetorp B, Bendahl PO, Borg A, Brun E, Mertens F, Ohlsson T, Rennstam K, Wennerberg J, Wahlberg P (2009) Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck. J Exp Clin Cancer Res 28:17. doi:10.1186/1756-9966-28-17 PubMedCrossRef Henriksson E, Kjellen E, Baldetorp B, Bendahl PO, Borg A, Brun E, Mertens F, Ohlsson T, Rennstam K, Wennerberg J, Wahlberg P (2009) Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck. J Exp Clin Cancer Res 28:17. doi:10.​1186/​1756-9966-28-17 PubMedCrossRef
Zurück zum Zitat Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Penault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074. doi:10.1200/JCO.2008.21.3744 PubMedCrossRef Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Penault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074. doi:10.​1200/​JCO.​2008.​21.​3744 PubMedCrossRef
Zurück zum Zitat Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA III, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25(22):3230–3237. doi:10.1200/JCO.2006.10.5437 PubMedCrossRef Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA III, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25(22):3230–3237. doi:10.​1200/​JCO.​2006.​10.​5437 PubMedCrossRef
Zurück zum Zitat Kochupurakkal BS, Harari D, Di-Segni A, Maik-Rachline G, Lyass L, Gur G, Kerber G, Citri A, Lavi S, Eilam R, Chalifa-Caspi V, Eshhar Z, Pikarsky E, Pinkas-Kramarski R, Bacus SS, Yarden Y (2005) Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem 280(9):8503–8512. doi:10.1074/jbc.M413919200 PubMedCrossRef Kochupurakkal BS, Harari D, Di-Segni A, Maik-Rachline G, Lyass L, Gur G, Kerber G, Citri A, Lavi S, Eilam R, Chalifa-Caspi V, Eshhar Z, Pikarsky E, Pinkas-Kramarski R, Bacus SS, Yarden Y (2005) Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem 280(9):8503–8512. doi:10.​1074/​jbc.​M413919200 PubMedCrossRef
Zurück zum Zitat Maurizi M, Almadori G, Ferrandina G, Distefano M, Romanini ME, Cadoni G, Benedetti-Panici P, Paludetti G, Scambia G, Mancuso S (1996) Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer 74(8):1253–1257PubMedCrossRef Maurizi M, Almadori G, Ferrandina G, Distefano M, Romanini ME, Cadoni G, Benedetti-Panici P, Paludetti G, Scambia G, Mancuso S (1996) Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer 74(8):1253–1257PubMedCrossRef
Zurück zum Zitat Oliveras-Ferraros C, Vall-Llovera AM, Salip DC, Vazquez-Martin A, Cufi S, Queralt B, Martin-Castillo B, Brunet J, de Llorens R, Menendez JA (2010) Evolution of the predictive markers amphiregulin and epiregulin mRNAs during long-term cetuximab treatment of KRAS wild-type tumor cells. Invest New Drugs. doi:10.1007/s10637-010-9612-2 Oliveras-Ferraros C, Vall-Llovera AM, Salip DC, Vazquez-Martin A, Cufi S, Queralt B, Martin-Castillo B, Brunet J, de Llorens R, Menendez JA (2010) Evolution of the predictive markers amphiregulin and epiregulin mRNAs during long-term cetuximab treatment of KRAS wild-type tumor cells. Invest New Drugs. doi:10.​1007/​s10637-010-9612-2
Zurück zum Zitat Tinhofer I, Klinghammer K, Weichert W, Knodler M, Stenzinger A, Gauler T, Budach V, Keilholz U (2011) Expression of amphiregulin and EGFRvIII affect outcome of patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. Clin Cancer Res 17(15):5197–5204. doi:10.1158/1078-0432.CCR-10-3338 PubMedCrossRef Tinhofer I, Klinghammer K, Weichert W, Knodler M, Stenzinger A, Gauler T, Budach V, Keilholz U (2011) Expression of amphiregulin and EGFRvIII affect outcome of patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. Clin Cancer Res 17(15):5197–5204. doi:10.​1158/​1078-0432.​CCR-10-3338 PubMedCrossRef
Zurück zum Zitat Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11):1116–1127. doi:10.1056/NEJMoa0802656 PubMedCrossRef Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359(11):1116–1127. doi:10.​1056/​NEJMoa0802656 PubMedCrossRef
Zurück zum Zitat Yamatodani T, Ekblad L, Kjellén E, Johnsson A, Mineta H, Wennerberg J (2009) Epidermal growth factor receptor status and persistent activation of Akt and p44/42 MAPK pathways correlate with the effect of cetuximab in head and neck and colon cancer cell lines. J Cancer Res Clin Oncol 135(3):395–402. doi:10.1007/s00432-008-0475-2 PubMedCrossRef Yamatodani T, Ekblad L, Kjellén E, Johnsson A, Mineta H, Wennerberg J (2009) Epidermal growth factor receptor status and persistent activation of Akt and p44/42 MAPK pathways correlate with the effect of cetuximab in head and neck and colon cancer cell lines. J Cancer Res Clin Oncol 135(3):395–402. doi:10.​1007/​s00432-008-0475-2 PubMedCrossRef
Zurück zum Zitat Yonesaka K, Zejnullahu K, Lindeman N, Homes AJ, Jackman DM, Zhao F, Rogers AM, Johnson BE, Jänne PA (2008) Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Clin Cancer Res 14(21):6963–6973. doi:10.1158/1078-0432.CCR-08-0957 PubMedCrossRef Yonesaka K, Zejnullahu K, Lindeman N, Homes AJ, Jackman DM, Zhao F, Rogers AM, Johnson BE, Jänne PA (2008) Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Clin Cancer Res 14(21):6963–6973. doi:10.​1158/​1078-0432.​CCR-08-0957 PubMedCrossRef
Metadaten
Titel
Autocrine epidermal growth factor receptor ligand production and cetuximab response in head and neck squamous cell carcinoma cell lines
verfasst von
Goro Oshima
Johan Wennerberg
Takashi Yamatodani
Elisabeth Kjellén
Hiroyuki Mineta
Anders Johnsson
Lars Ekblad
Publikationsdatum
01.03.2012
Verlag
Springer-Verlag
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 3/2012
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-011-1127-5

Weitere Artikel der Ausgabe 3/2012

Journal of Cancer Research and Clinical Oncology 3/2012 Zur Ausgabe

Adjuvante Immuntherapie verlängert Leben bei RCC

25.04.2024 Nierenkarzinom Nachrichten

Nun gibt es auch Resultate zum Gesamtüberleben: Eine adjuvante Pembrolizumab-Therapie konnte in einer Phase-3-Studie das Leben von Menschen mit Nierenzellkarzinom deutlich verlängern. Die Sterberate war im Vergleich zu Placebo um 38% geringer.

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

25.04.2024 NSCLC Nachrichten

Das Risiko für Rezidiv oder Tod von Patienten und Patientinnen mit reseziertem ALK-positivem NSCLC ist unter einer adjuvanten Therapie mit dem Tyrosinkinase-Inhibitor Alectinib signifikant geringer als unter platinbasierter Chemotherapie.

Bei Senioren mit Prostatakarzinom auf Anämie achten!

24.04.2024 DGIM 2024 Nachrichten

Patienten, die zur Behandlung ihres Prostatakarzinoms eine Androgendeprivationstherapie erhalten, entwickeln nicht selten eine Anämie. Wer ältere Patienten internistisch mitbetreut, sollte auf diese Nebenwirkung achten.

ICI-Therapie in der Schwangerschaft wird gut toleriert

Müssen sich Schwangere einer Krebstherapie unterziehen, rufen Immuncheckpointinhibitoren offenbar nicht mehr unerwünschte Wirkungen hervor als andere Mittel gegen Krebs.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.