Tyrosine kinase inhibitors protect the salivary gland from radiation damage by increasing DNA double-strand break repair

Abstract

We have previously shown that the tyrosine kinase inhibitors (TKIs) dasatinib and imatinib can protect salivary glands from irradiation (IR) damage without impacting tumor therapy. However, how they induce this protection is unknown. Here we show that TKIs mediate radioprotection by increasing the repair of DNA double-stranded breaks. DNA repair in IR-treated parotid cells, but not oral cancer cells, occurs more rapidly following pretreatment with imatinib or dasatinib and is accompanied by faster formation of DNA damage-induced foci. Similar results were observed in the parotid glands of mice pretreated with imatinib prior to IR, suggesting that TKIs “prime” cells for DNA repair. Mechanistically, we observed that TKIs increased IR-induced activation of DNA-PK, but not ATM. Pretreatment of parotid cells with the DNA-PK inhibitor NU7441 reversed the increase in DNA repair induced by TKIs. Reporter assays specific for homologous recombination (HR) or nonhomologous end joining (NHEJ) verified regulatation of both DNA repair pathways by imatinib. Moreover, TKIs also increased basal and IR-induced expression of genes associated with NHEJ (DNA ligase 4, Artemis, XLF) and HR (Rad50, Rad51 and BRCA1); depletion of DNA ligase 4 or BRCA1 reversed the increase in DNA repair mediated by TKIs. In addition, TKIs increased activation of the ERK survival pathway in parotid cells, and ERK was required for the increased survival of TKI-treated cells. Our studies demonstrate a dual mechanism by which TKIs provide radioprotection of the salivary gland tissues and support exploration of TKIs clinically in head and neck cancer patients undergoing IR therapy. We have previously shown that the tyrosine kinase inhibitors (TKIs) dasatinib and imatinib can protect salivary glands from irradiation (IR) damage without impacting tumor therapy. However, how they induce this protection is unknown. Here we show that TKIs mediate radioprotection by increasing the repair of DNA double-stranded breaks. DNA repair in IR-treated parotid cells, but not oral cancer cells, occurs more rapidly following pretreatment with imatinib or dasatinib and is accompanied by faster formation of DNA damage-induced foci. Similar results were observed in the parotid glands of mice pretreated with imatinib prior to IR, suggesting that TKIs “prime” cells for DNA repair. Mechanistically, we observed that TKIs increased IR-induced activation of DNA-PK, but not ATM. Pretreatment of parotid cells with the DNA-PK inhibitor NU7441 reversed the increase in DNA repair induced by TKIs. Reporter assays specific for homologous recombination (HR) or nonhomologous end joining (NHEJ) verified regulatation of both DNA repair pathways by imatinib. Moreover, TKIs also increased basal and IR-induced expression of genes associated with NHEJ (DNA ligase 4, Artemis, XLF) and HR (Rad50, Rad51 and BRCA1); depletion of DNA ligase 4 or BRCA1 reversed the increase in DNA repair mediated by TKIs. In addition, TKIs increased activation of the ERK survival pathway in parotid cells, and ERK was required for the increased survival of TKI-treated cells. Our studies demonstrate a dual mechanism by which TKIs provide radioprotection of the salivary gland tissues and support exploration of TKIs clinically in head and neck cancer patients undergoing IR therapy. Most patients diagnosed with head and neck cancer (HNC) in the United States are treated with irradiation (IR) therapy alone or IR in combination with surgery or chemotherapy. While IR is targeted to the tumor, damage to nontumor adjacent tissues such as oral mucosa and the salivary glands also occurs, and in some cases can limit the course of therapy (1Gudkov S.V. Garmash S.A. Shtarkman I.N. Chernikov A.V. Karp O.E. Bruskov V.I. Long-lived protein radicals induced by X-ray irradiation are the source of reactive oxygen species in aqueous medium.Dokl Biochem. Biophys. 2010; 430: 1-4Crossref PubMed Scopus (29) Google Scholar). This is despite improvements in radiation delivery such as intensity-modulated radiation therapy (IMRT), which enable more precise delivery of IR to the tumor (2Hawkins P.G. Lee J.Y. Mao Y. Li P. Green M. Worden F.P. Swiecicki P.L. Mierzwa M.L. Spector M.E. Schipper M.J. Eisbruch A. Sparing all salivary glands with IMRT for head and neck cancer: Longitudinal study of patient-reported xerostomia and head-and-neck quality of life.Radiother. Oncol. 2018; 126: 68-74Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Permanent damage to the salivary glands occurs in up to 40% of HNC patients and can have a significant impact on quality of life, oral health, and nutrition (3Jensen S.B. Vissink A. Limesand K.H. Reyland M.E. Salivary gland Hypofunction and xerostomia in head and neck radiation patients.J Natl. Cancer Inst. Monogr. 2019; 2019: lgz01Crossref Scopus (27) Google Scholar). The free radical scavenger Amifostine is the only radioprotector currently available for sparing oral tissues, but it is not widely used due to systemic toxicity (4Soref C.M. Hacker T.A. Fahl W.E. A new orally active, aminothiol radioprotector-free of nausea and hypotension side effects at its highest radioprotective doses.Int. J. Radiat. Oncol. Biol. Phys. 2012; 82: e701-e707Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). This underscores the need for new radioprotective therapies that can prevent or mitigate IR damage to nontumor tissues without impacting tumor eradication. Tyrosine kinases regulate many biological for and and are in cancer A. tyrosine kinases and pathways as for cancer The of 2018; PubMed Scopus (27) Google A. cancer and 2018; PubMed Scopus Google Scholar). and dasatinib are used clinically to and A. M. Y. M. imatinib for patients with or 2018; PubMed Scopus Google on the of imatinib and the of cancer PubMed Scopus Google as a of targeted Cancer PubMed Scopus Google M. A. Cancer PubMed Scopus Google shown to HNC in A. J. study of dasatinib in the of head and neck PubMed Scopus Google Y. A. M. A study of for of head and neck salivary Oncol. PubMed Scopus Google Scholar). studies from and demonstrate that dasatinib and imatinib can protect nontumor in mice treated with IR or M. M. of the pathway from PubMed Scopus Google M. P. M. and dasatinib protect radiation by of Oncol. Full Text Full Text PDF PubMed Scopus Google J. Reyland M.E. tyrosine of protein kinase the salivary gland from radiation Biol. Full Text Full Text PDF PubMed Scopus Google Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). dasatinib can protect IR-induced in mice M. P. M. and dasatinib protect radiation by of Oncol. Full Text Full Text PDF PubMed Scopus Google and imatinib can protect from M. M. of the pathway from PubMed Scopus Google Scholar). Our studies show and radioprotection of salivary gland and in is or IR Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). TKIs mediate radioprotection of the salivary tissues in of suggesting that in this tyrosine kinases are required for J. Reyland M.E. tyrosine of protein kinase the salivary gland from radiation Biol. Full Text Full Text PDF PubMed Scopus Google Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). the of dasatinib and imatinib in in tissues, but in some of the for radioprotection by TKIs is IR a of DNA with double-stranded the DNA and PubMed Scopus Google Scholar). repair by nonhomologous end joining (NHEJ) or homologous recombination (HR) can increase survival and the of cells. Here we have the that TKIs provide radioprotection by the repair of IR-induced DNA the of the tumor studies have both for radioprotection and for tumor therapy. We have previously shown that TKIs in and provide radioprotection in J. Reyland M.E. tyrosine of protein kinase the salivary gland from radiation Biol. Full Text Full Text PDF PubMed Scopus Google Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). are the of DNA induced by IR, and repair is for survival DNA and PubMed Scopus Google Scholar). the that dasatinib and imatinib provide radioprotection by increasing we used a DNA to DNA damage IR, of DNA repair. We show that pretreatment of salivary cells with dasatinib or imatinib results in more of DNA as with cells A and IR, DNA damage is in dasatinib and in cells, with cells treated with IR alone IR, DNA damage is in dasatinib and in cells with cells treated with IR that IR-induced DNA repair is not in TKI-treated HNC cells, we the head and neck and dasatinib imatinib increased repair of IR-induced DNA damage in and in DNA damage was increased following a pretreatment with TKIs with cells and with alone for 4 increased DNA damage up to in cells with a of TKIs in DNA damage in cancer cells DNA damage and DNA for new PubMed Scopus Google Scholar). This studies that show of TKIs for radioprotection of salivary gland cells, without survival of in or in Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). We how TKIs impact DNA repair by of and which of repair DNA double-stranded induce on Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In dasatinib or cells, both and increased more rapidly delivery of IR with cells IR, were increased by dasatinib and by imatinib and were increased by dasatinib and by imatinib and IR, and were in and cells. However, at IR, were and and were and in dasatinib and cells, with IR alone A and The faster formation of and at and increased at that repair of is more and that pretreatment with TKIs “prime” salivary cells for activation of DNA repair TKIs increase IR-induced in mice were pretreated with imatinib prior to delivery of IR and the parotid glands were at IR results in a increase in by which was by at 4 Similar to cells in of at was increased in mice pretreated with imatinib and more formation and repair. 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Biol. PubMed Scopus Google Scholar). the of on survival we TKIs regulate and this is on ERK shown in both imatinib and dasatinib protect IR-treated cells from and this protection is in on that ERK activation by TKIs is for survival and that this mediated by and of in to increased DNA to to radioprotection by TKIs. tissues, mucosa and tissues in the oral are in patients undergoing IR therapy for While TKIs are widely used for cancer studies from and also show that some TKIs can protect IR and damage M. M. of the pathway from PubMed Scopus Google M. P. M. and dasatinib protect radiation by of Oncol. Full Text Full Text PDF PubMed Scopus Google J. Reyland M.E. tyrosine of protein kinase the salivary gland from radiation Biol. Full Text Full Text PDF PubMed Scopus Google Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). 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PubMed Scopus Google and increase NHEJ M. and of cells as a to study DNA repair in PubMed Scopus Google Scholar). by in of NHEJ and TKIs induce a DNA in increased Our studies show that TKIs induce more and more repair of IR-induced DNA We that dasatinib or imatinib salivary cells for DNA repair in by increasing basal expression of required for NHEJ and HR 4, This is by that formation of HR and DNA damage occurs more rapidly in cells A and Our studies that imatinib and dasatinib have but not radioprotective effects in activation of imatinib is a more of all HR and NHEJ repair genes imatinib more ERK and DNA-PK, and results in more formation of DNA-PK foci. a DNA repair we show that imatinib not DNA repair by HR and We have increased formation of IR-induced in in mice pretreated with imatinib prior to the increase in in the mice was only on in it is that this from DNA repair. 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PubMed Scopus (27) Google Scholar). from that TKIs can salivary gland IR, suggesting that a of cells and that the of cells is Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). In to of DNA we show that both dasatinib and imatinib increase basal ERK activation a mechanism for cells. While ERK activation is required for the increased survival in cells treated with imatinib or we that it is not required for IR-induced survival but for survival ERK also in and IR-treated cells. This is with studies that show activation of ERK can protect cells from M.J. J. Biol. PubMed Scopus Google Scholar). we have previously shown that of ERK formation in cancer cells by increasing Reyland M.E. expression and of cancer PubMed Scopus Google Scholar). In but not also increased This in imatinib is a more of ERK in the of that dasatinib and imatinib not provide radioprotection to HNC cells. In both imatinib and dasatinib increased DNA damage in HNC This is with from that IR in Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). both dasatinib and imatinib have used widely in the to specific and shown HNC A. J. study of dasatinib in the of head and neck PubMed Scopus Google Y. A. M. A study of for of head and neck salivary Oncol. PubMed Scopus Google Scholar). Our studies provide studies from that show TKIs provide and radioprotection of salivary gland in and that imatinib salivary gland following irradiation Reyland M.E. Tyrosine kinase inhibitors protect the salivary gland from radiation damage by activation of protein kinase Cancer PubMed Scopus Google Scholar). 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