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

Ernst, Anne; Anders, Heike; Kapfhammer, Heidi; Orth, Michael; Hennel, Roman; Seidl, Karin; Winssinger, Nicolas; Belka, Claus; Unkel, Steffen; Lauber, Kirsten

doi:10.1016/j.canlet.2015.05.024

Cited by 39 publications

(38 citation statements)

References 49 publications

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“…Indeed, treatment of colorectal cancer cells with NW457 resulted in rapid degradation of ATM and CHK1, two essential upstream kinases of the DNA damage response. This is in accordance with findings of other studies, which showed that targeting HSP90 with small-molecule inhibitors induces the destabilization of different DNA damage response regulators, including ATM, CHK1, DNA-dependent protein kinase (DNA-PK), DNA repair protein RAD51 homologue 1 (RAD51), breast cancer 1 (BRCA1), and others [12, 13, 15, 19, 49, 57, 58]. Importantly, homologous recombination and non-homologous end joining, the two major mechanisms which operate to repair irradiation-induced DNA double strand breaks, appear to be affected to comparable extents [12, 13, 49, 59, 60].…”

Section: Discussionsupporting

confidence: 92%

“…To analyze the kinetics of DNA damage repair in the presence or absence of NW457 cells were stained for γH2AX as described previously [57]. Briefly, 2.5x 10 5 HCT116 cells were seeded into 24-well plates supplemented with coverslips.…”

Section: Methodsmentioning

confidence: 99%

“…Cellular senescence was detected by using a FACS-based activity test for senescence-associated β-galactosidase with the fluorogenic substrate 5-dodecanoylaminofluorescein-di-β-galactopyranoside (C12-FDG, Life Technologies) as described previously [57]. Briefly, following lysosomal alkalinization with 100 nM bafilomycin A1 (Tocris R&D Systems, Heidelberg, Germany), 50 μM C12-FDG was added, and substrate conversion was allowed for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

et al. 2016

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The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

et al. 2016

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“…In vitro, inhibition of Hsp90 decreased cell viability and inactivated the mTOR pathway. In a study by Ernst et al [71] expression of HSP90 was found to be associated with radioresistance by comparing transcriptomes of sarcoma cell lines with radioresistance scores (generated by principal component analysis). Expression of HSP90 strongly correlated with high radioresistance scores, and subsequent HSP90 inhibition sensitized radioresistant sarcoma cell lines to radiation therapy.…”

Section: Targeted Therapymentioning

confidence: 99%

Advances in sarcoma diagnostics and treatment

2016

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The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed. Transcriptome sequencing techniques have brought forward new diagnostic tools for identifying fusions and/or characterizing unclassified entities. Next-generation sequencing and advanced molecular techniques were also applied to identify potential targets for directed and epigenetic therapy, where preclinical studies reported results for agents active within the receptor tyrosine kinase, mTOR, Notch, Wnt, Hedgehog, Hsp90, and MDM2 signaling networks. At the level of clinical practice, modest developments were seen for some sarcoma subtypes in conventional chemotherapy and in therapies targeting the pathways activated by various receptor tyrosine kinases. In the burgeoning field of immune therapy, sarcoma work is in its infancy; however, elaborate protocols for immune stimulation are being explored, and checkpoint blockade agents advance from preclinical models to clinical studies.

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“…204 Further, RT often primarily induces senescent tumor cells. 218 The impact of the senescence-associated secretory phenotype (SASP) on tumor progression is under current intensive investigation. 219 Other prominent DAMPs are HSPs, especially HSP70.…”

Section: Review Toxicology Researchmentioning

confidence: 99%

Key mechanisms involved in ionizing radiation-induced systemic effects. A current review

Mavragani

Laskaratou

Frey

et al. 2015

Toxicology Research

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

Cited by 39 publications

References 49 publications

A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

Advances in sarcoma diagnostics and treatment

Key mechanisms involved in ionizing radiation-induced systemic effects. A current review

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