Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-{delta}

In patients undergoing irradiation therapy, injury to non-tumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined Protein Kinase C-delta (PKC) as a regulator of DNA damage induced apoptosis and have shown that phosphorylation of PKC by c-Abl and c-Src activates its pro-apoptotic function.  Here we have explored the use of tyrosine kinase inhibitors (TKIs) of c-Src and c-Abl to block activation of PKC for radioprotection of the salivary gland.  Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKC and inhibited IR-induced apoptosis in vitro.  To determine if TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation. Delivery of dasatinib or imatinib within 3 hours of a single or fractionated dose of irradiation resulted in >75% protection of salivary gland function at 60 days. Continuous dosing with dasatinib extended protection to at least 5 months and correlated with histological evidence of salivary gland acinar cell regeneration. Pretreatment with TKIs had no impact on clonogenic survival of HNSCC cells, and in mice harboring HNSCC cell derived xenografts, combining dasatinib or imatinib with fractionated irradiation did not enhance tumor growth.  Our studies indicate that TKIs may be useful clinically to protect non-tumor tissue in HNC patients undergoing radiation therapy, without negatively impacting cancer treatment.

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