title: HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas.
abstract: Radiotherapy is an essential part of multi-modal treatment for soft tissue sarcomas. Treatment failure is commonly attributed to radioresistance, but comprehensive analyses of radiosensitivity are not available, and suitable biomarkers or candidates for targeted radiosensitization are scarce. Here, we systematically analyzed the intrinsic radioresistance of a panel of soft tissue sarcoma cell lines, and extracted scores of radioresistance by principal component analysis (PCA). To identify molecular markers of radioresistance, transcriptomic profiling of DNA damage response regulators was performed. The expression levels of HSP90 and its clients ATR, ATM, and NBS1 revealed strong, positive correlations with the PCA-derived radioresistance scores. Their functional involvement was addressed by HSP90 inhibition, which preferentially sensitized radioresistant sarcoma cells and was accompanied by delayed γ-H2AX foci clearance and HSP90 client protein degradation. The induction of apoptosis and necrosis was not significantly enhanced, but increased levels of basal and irradiation-induced senescence upon HSP90 inhibition were detected. Finally, evaluation of our findings in the TCGA soft tissue sarcoma cohort revealed elevated expression levels of HSP90, ATR, ATM, and NBS1 in a relevant subset of cases with particularly poor prognosis, which might preferentially benefit from HSP90 inhibition in combination with radiotherapy in the future.
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Ernst
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Anders
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kapfhammer
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Orth
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Hennel
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Seidl
authors.affiliation: Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Winssinger
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Unkel
authors.affiliation: Clinic for Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: kirsten.lauber@med.uni-muenchen.de.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D016922:Cellular Senescence / Q000235:genetics; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis; D025341:Principal Component Analysis; D011836:Radiation Tolerance / Q000235:genetics*; D012509:Sarcoma / Q000532:radiotherapy*; D012983:Soft Tissue Neoplasms / Q000532:radiotherapy*
chemical_list: D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: HSP90 inhibition; Radioresistance; Radiosensitization; Radiotherapy; Soft tissue sarcoma