291 TAS-116, a Novel, Orally Bioavailable HSP90a/β Selective Inhibitor Demonstrates Highly Potent Antitumor Activity in Preclinical Models with a Favorable PK Profile

Abstract

be one of the most active standard chemotherapeutic agents against osteosarcoma. Long term survival (>5years) for relapsed disease is poor at less than 20%. The role of second line chemotherapy, including etoposide, is ill defined without a standard regimen and drug resistance is common. Double strand breaks (DSBs) are considered a lethal cell lesion. DNAPK is required for the non-homologous end joining repair of DSBs. DNAPK inhibitors have been shown to potentiate the effects of topoisomerase II poisons. We wished to investigate the potential of DNA-PK inhibitor NU7441 as a chemo-potentiating agent in osteosarcoma. Material and Methods: Paired SJSA-1(p53wt) and SM6R1 (p53mut) osteosarcoma cell lines were treated with both etoposide and doxorubicin alone and in combination with the DNA-PK inhibitor NU7441. Growth inhibition/cytotoxicity was measured through sulforhodamine B assay (SRB) and colony formation assay with GI50 and LC50 values calculated respectively. Results: Five day exposure to NU7441 (1mM) in combination with etoposide induced an average 9-fold potentiation of etoposide and 8-fold potentiation of doxorubicin when compared to treatment with drug alone in SJSA-1 cells. Both etoposide and doxorubicin exhibited a 5-fold potentiation when treated in conjunction with NU7441 in SM6R1 cells. Conclusions: NU7441 justifies the investigation of DNA-PK inhibitors as a chemo-potentiating agent in osteosarcoma.