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Simple Summary  Our previous preclinical trial in a head and neck squamous cell carcinoma (HNSCC) xenograft model showed a high potential for the improvement of curative treatment outcome upon the combination treatment of a radiolabeled (Yttrium-90) anti-EGFR antibody (Cetuximab) and external radiotherapy. We aim to elucidate the molecular response of HNSCC tumors upon this combination. Here, we show that the combination treatment leads to an increasing number and complexity of DNA double strand breaks. The upregulation of p21 cip1/waf1  expression and cleaved caspase-3 suggest a blockage of cell cycle transition and an induction of programmed cell death. Collectively, a complex interplay between molecular mechanisms involved in cell death induction, cell cycle arrest, and DNA double strand break repair accounts for the beneficial potential using Yttrium-90-Cetuximab in combination with external radiotherapy.Abstract  Combination treatment of molecular targeted and external radiotherapy is a promising strategy and was shown to improve local tumor control in a HNSCC xenograft model. To enhance the therapeutic value of this approach, this study investigated the underlying molecular response. Subcutaneous HNSCC FaDu DD  xenografts were treated with single or combination therapy (X-ray: 0, 2, 4 Gy; anti-EGFR antibody (Cetuximab) (un-)labeled with Yttrium-90 ( 90 Y)). Tumors were excised 24 h post respective treatment. Residual DNA double strand breaks (DSB), mRNA expression of DNA damage response related genes, immunoblotting, tumor histology, and immunohistological staining were analyzed. An increase in number and complexity of residual DNA DSB was observed in FaDu DD  tumors exposed to the combination treatment of external irradiation and  90 Y-Cetuximab relative to controls. The increase was observed in a low oxygenated area, suggesting the expansion of DNA DSB damages. Upregulation of genes encoding p21 cip1/waf1  ( CDKN1A ) and GADD45α ( GADD45A ) was determined in the combination treatment group, and immunoblotting as well as immunohistochemistry confirmed the upregulation of p21 cip1/waf1 . The increase in residual γH2AX foci leads to the blockage of cell cycle transition and subsequently to cell death, which could be observed in the upregulation of p21 cip1/waf1  expression and an elevated number of cleaved caspase-3 positive cells. Overall, a complex interplay between DNA damage repair and programmed cell death accounts for the potential benefit of the combination therapy using  90 Y-Cetuximab and external radiotherapy.

Molecular Response to Combined Molecular- and External Radiotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC)