Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing’s sarcoma cells

Abstract Introduction Ewing's sarcoma is an aggressive childhood malignancy whose outcome has not substantially improved over the last two decades. In this study, combination treatments of HSP90 inhibitor AUY922 with either ATR VE821 or ATM KU55933 were investigated for their effectiveness in cells. Methods Effects determined p53 wild-type and null cell lines by flow cytometric analyses death, mitochondrial depolarization cell-cycle distribution as well fluorescence transmission electron microscopy. They molecularly characterized gene protein expression profiling, quantitative whole proteome analysis. Results alone induced DNA damage, apoptosis ER stress, while reducing abundance repair proteins. The led to strong induction independent cellular status, yet based on different molecular mechanisms. cells activated pro-apoptotic transcription underwent mitochondria-mediated apoptosis, accumulated higher levels stress autophagy, eventually leading apoptosis. Impaired PI3K/AKT/mTOR signaling further contributed antineoplastic effects VE821. contrast, did produce a cooperative effect. Conclusion Our study reveals that treatment may be effective therapeutic approach irrespective status.