Simultaneous β1 integrin-EGFR Targeting and Radiosensitization of Human Head and Neck Cancer

Eke, Iris; Zscheppang, Katja; Dickreuter, Ellen; Hickmann, Linda; Mazzeo, E.; Unger, Kristian; Krause, Mechthild; Cordes, Nils

doi:10.1093/jnci/dju419

Cited by 78 publications

(105 citation statements)

References 62 publications

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“…[3][4][5][6] We and other groups have demonstrated enhanced tumor cell sensitivity to radiotherapy, chemotherapy and molecular drugs as a result of antibody-mediated β1 integrin targeting in various preclinical cancer models including head and neck, lung, brain, breast and leukemia. [7][8][9][10][11][12] Integrins are transmembrane cell adhesion receptors for ECM proteins. 18 α and 8 β integrin subunits can form 24 different α/β integrin heterodimers by non-covalent binding.…”

Section: Introductionmentioning

confidence: 99%

Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

et al. 2015

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β1 Integrin-mediated cell-extracellular matrix interactions allow cancer cell survival and confer therapy resistance. It was shown that inhibition of β1 integrins sensitizes cells to radiotherapy. Here, we examined the impact of β1 integrin targeting on the repair of radiation-induced DNA double-strand breaks (DSBs). β1 Integrin inhibition was accomplished using the monoclonal antibody AIIB2 and experiments were performed in three-dimensional cell cultures and tumor xenografts of human head and neck squamous cell carcinoma (HNSCC) cell lines. AIIB2, X-ray irradiation, small interfering RNA-mediated knockdown and Olaparib treatment were performed and residual DSB number, protein and gene expression, non-homologous end joining (NHEJ) activity as well as clonogenic survival were determined. β1 Integrin targeting impaired repair of radiogenic DSB (γH2AX/53BP1, pDNA-PKcs T2609 foci) in vitro and in vivo and reduced the protein expression of Ku70, Rad50 and Nbs1. Further, we identified Ku70, Ku80 and DNA-PKcs but not poly(ADP-ribose) polymerase (PARP)-1 to reside in the β1 integrin pathway. Intriguingly, combined inhibition of β1 integrin and PARP using Olaparib was significantly more effective than either treatment alone in non-irradiated and irradiated HNSCC cells. Here, we support β1 integrins as potential cancer targets and highlight a regulatory role for β1 integrins in the repair of radiogenic DNA damage via classical NHEJ. Further, the data suggest combined targeting of β1 integrin and PARP as promising approach for radiosensitization of HNSCC.

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Section: Introductionmentioning

confidence: 99%

Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

et al. 2015

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“…Based on the promising simultaneous b1 integrin/EGFR targeting results we have gained in head and neck cancers [18], we evaluated the radiosensitizing and anti-invasive potential of this approach in CRC cells. As shown previously, the 3D lrECM environment mimics the original growth conditions well.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to hampering invasion, we and others have demonstrated that b1 integrin targeting enhances radiochemosensitivity in head and neck cancer, glioblastoma, lung cancer, pancreatic cancer, breast cancer and leukemia [10][11][12][13][14][15][16][17]. In head and neck cancers, simultaneous b1 integrin/EGFR targeting elicited stronger radiosensitization than monotherapies [18].…”

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confidence: 85%

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EGFR and β1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion

Poschau

Dickreuter

Singh-Müller

et al. 2015

Radiotherapy and Oncology

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“…Since the development of techniques like the spheroid model or the laminin-rich extracellular matrix (lrECM)-based cell cultures, several studies have shown that the results generated using these 3D assays have higher similarity with in vivo data than conventional 2D cell culture assays [1-7]. Especially in regard to signal transduction, the molecular processes in 2D and 3D cultured cells seem to differ significantly [4,5,8,9].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of signal transduction in three-dimensional ECM-based tumor cell cultures

Eke

Hehlgans

Zong

et al. 2015

JBM

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Analysis of signal transduction and protein phosphorylation is fundamental to understanding physiological and pathological cell behavior and identifying novel therapeutic targets. Despite the fact that the use of physiological three-dimensional cell culture assays is increasing, 3D proteomics and phosphoproteomics remain challenging due to difficulties with easy, robust and reproducible sample preparation. Here, we present an easy-to-perform, reliable and time-efficient method for the production of 3D cell lysates that does not compromise cell adhesion before cell lysis. The samples can be used for western blotting as well as phosphoproteome array technology. This technique will be of interest for researchers working in all fields of biology and drug development.

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Simultaneous β1 integrin-EGFR Targeting and Radiosensitization of Human Head and Neck Cancer

Abstract: Concomitant targeting of β1 integrin and EGFR seems a powerful and promising approach to overcome radioresistance of HNSCCs.

Cited by 78 publications

References 62 publications

Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

EGFR and β1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion

Comprehensive analysis of signal transduction in three-dimensional ECM-based tumor cell cultures

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