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Published on: April 22, 2019
Simultaneous β1 integrin-EGFR targeting and radiosensitization of human head and neck cancer
Iris Eke1, Katja Zscheppang1, Ellen Dickreuter1
1OncoRay, National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany and Helmholtz-Zentrum Dresden, Rossendorf, Dresden, Germany (IE, KZ, ED, LH, EM, MK, NC); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany (IE, MK, NC); Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden, Rossendorf, Dresden, Germany (KZ); Research Unit Radiation Cytogenetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (KU); Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer," Helmholtz-Zentrum München, Neuherberg, Germany (KU); German Cancer Consortium (DKTK), Dresden, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany (MK, NC); Institute of Radiooncology, Helmholtz-Zentrum Dresden, Rossendorf, Dresden, Germany (MK, NC).
Background:
Signaling from integrins and receptor tyrosine kinases (RTKs) contributes substantially to therapy resistance of malignant tumors. We investigated simultaneous β1 integrin-epidermal growth factor receptor (EGFR) targeting plus radiotherapy in human head and neck squamous cell carcinomas (HNSCCs).
Methods:
Ten HNSCC cell lines were grown in three-dimensional laminin-rich extracellular matrix cell cultures and two of them as tumor xenografts in nude mice (n = 12-16 per group). Targeting of β1 integrin and EGFR with monoclonal inhibitory antibodies (AIIB2 and cetuximab, respectively) was combined with x-ray irradiation. Clonogenic survival, tumor growth, and tumor control (evaluated by Kaplan-Meier analysis), apoptosis, phosphoproteome (interactome, network betweeness centrality analysis), receptor expression (immunohistochemistry), and downstream signaling (western blotting) were assessed. Various mutants of the integrin signaling mediator focal adhesion kinase (FAK) were employed for mechanistic studies. All statistical tests were two-sided.
Results:
Compared with β1 integrin or EGFR single inhibition, combined β1 integrin-EGFR targeting resulted in enhanced cytotoxicity and radiosensitization in eight out of 10 tested HNSCC cell lines, which responded with an FAK dephosphorylation after β1 integrin inhibition. In vivo, simultaneous anti-β1 integrin/anti-EGFR treatment and radiotherapy of UTSCC15 responder xenografts enabled better tumor control compared with anti-EGFR monotherapy and irradiation (hazard ratio [HR] = 6.9, 95% confidence interval [CI] = 1.6 to 30.9, P = .01), in contrast to the SAS nonresponder tumor model (HR = 0.9, 95% CI = 0.4 to 2.3, P = .83). Mechanistically, a protein complex consisting of FAK- and Erk1-mediated prosurvival signals for radiation resistance, which was effectively compromised by β1 integrin and EGFR blocking.
Conclusions:
Concomitant targeting of β1 integrin and EGFR seems a powerful and promising approach to overcome radioresistance of HNSCCs.
Insights
Combining β1 integrin and epidermal growth factor receptor (EGFR) targeting with radiotherapy enhances cancer cell killing and tumor control in head and neck cancers. This approach overcomes radioresistance by disrupting prosurvival signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Integrin and receptor tyrosine kinase (RTK) signaling promote malignant tumor therapy resistance.
- Head and neck squamous cell carcinomas (HNSCCs) exhibit resistance to conventional treatments.
Purpose of the Study:
- To investigate the efficacy of simultaneous β1 integrin-epidermal growth factor receptor (EGFR) targeting combined with radiotherapy in HNSCCs.
- To elucidate the underlying mechanisms of radioresistance and the effects of combined targeted therapy.
Main Methods:
- Utilized 10 HNSCC cell lines in 3D cultures and xenografts in nude mice.
- Administered monoclonal antibodies targeting β1 integrin and EGFR alongside x-ray irradiation.
- Assessed clonogenic survival, tumor growth, tumor control, apoptosis, phosphoproteome, receptor expression, and downstream signaling, including focal adhesion kinase (FAK) mutants.
Main Results:
- Combined β1 integrin-EGFR targeting with radiotherapy enhanced cytotoxicity and radiosensitization in 8/10 HNSCC cell lines.
- In vivo studies showed improved tumor control in responder xenografts (UTSCC15) compared to EGFR monotherapy and irradiation (HR=6.9, P=.01).
- Mechanistically, the combination therapy disrupted FAK- and Erk1-mediated prosurvival signals crucial for radiation resistance.
Conclusions:
- Simultaneous targeting of β1 integrin and EGFR presents a potent strategy to overcome radioresistance in HNSCC.
- This combined approach holds promise for improving therapeutic outcomes in head and neck cancer patients.
