2nd ESTRO Forum 2013 S253 Purpose/Objective: Nuclear EGFR has been implicated in resistance to both radiation and EGFR-inhibition. Src family kinases (SFKs) are required for translocation of EGFR to the nucleus. We investigated whether inhibition of SFK via dasatinib can enhance the effect of radiotherapy in in vivo head and neck squamous cell carcinoma (HNSCC) models. Materials and Methods: Two HNSCC xenograft models, SCCNij153 and SCCNij202, were treated with dasatinib, radiation or both, and

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... effects on growth delay, EGFR signaling, DNA repair, hypoxia and proliferation were investigated. Results: Dasatinib and radiotherapy induced a significant growth delay in both HNSCC xenograft models, although to a lesser extent in SCCNij202. Dasatinib did not inhibit pAKT or pERK1/2, but did inhibit (p)DNA-PK. Moreover, dasatinib reduced radiation-induced DNA repair as shown by an increase of 53BP1 staining 24h after radiation. This effect on DNA repair was only observed in the cell compartment where pSFK was expressed; for SCCNij153 tumors in normoxic and hypoxic areas, for SCCNij202 tumors only in hypoxic areas. No consistent effects of dasatinib on hypoxia or proliferation were observed. Conclusions: Dasatinib enhances the effect of radiotherapy in vivo by inhibition of radiation-induced DNA repair and is a promising way to improve outcome in HNSCC patients.