HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas

•Intrinsic radioresistance of soft tissue sarcoma cell lines as measured by clonogenic survival varies substantially.•Scores of radioresistance were extracted by principal component analysis of clonogenic survival data.•mRNA levels of HSP90 and its clients ATR, ATM, and NBS1 reveal strong correlations with PCA-derived radioresistance scores.•HSP90 inhibition preferentially sensitizes radioresistant sarcoma cells.•Radiosensitization is accompanied by client protein degradation and delayed γ-H2AX foci clearance.•HSP90 inhibitor concentrations sufficient for radiosensitization do not affect irradiation-induced apoptosis or necrosis.•HSP90 inhibitor-mediated radiosensitization is accompanied by enforced basal and irradiation-induced senescence.•Soft tissue sarcomas with particularly poor prognosis reveal elevated levels of HSP90, ATR, ATM, and NBS1.•These aggressive soft tissue sarcomas might preferentially respond to HSP90 inhibition in combination with radiotherapy.