Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma

Steinmann, Sara; Gali‐Muhtasib, Hala; Huebner, K.; Al-Halabi, Racha; Merhi, Raghida Abou; Åman, Pierre; Agaimy, Abbas; Haller, Florian; Schneider‐Stock, Regine

doi:10.1016/j.canlet.2015.07.025

Cited by 10 publications

(17 citation statements)

References 32 publications

(39 reference statements)

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“…Although HSP90 is reported to be essential for VEGFR2 activation, which is one of the HSP90 client proteins, our results showed that HSP90 knock‐down did not affect VEGFR2 phosphorylation in angiosarcoma cell lines. In previous reports, the effects of HSP90 inhibitor on client proteins differed depending on the cell line in liposarcoma and pancreatic cancer . Based on these findings, our results indicate that the contribution of HSP90 to client proteins varies according to the type of cell, i.e.…”

Section: Discussionsupporting

confidence: 73%

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Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

et al. 2017

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Section: Discussionsupporting

confidence: 73%

“…In previous reports, the effects of HSP90 inhibitor on client proteins differed depending on the cell line in liposarcoma and pancreatic cancer. 49,50 Based on these findings, our results indicate that the contribution of HSP90 to client proteins varies according to the type of cell, i.e. endothelial cells or angiosarcoma cells.…”

Section: Discussionmentioning

confidence: 58%

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

et al. 2017

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“…It also caused growth cessation and death of MLS cells in vitro and extensive necrosis of xenografted MLS tumors. The cytostatic in vitro effects of HSP90 inhibition in MLS cell lines has recently been reported for an unrelated HSP90 inhibitor [ 47 ], confirming the MLS sensitivity to this class of drugs.…”

Section: Discussionmentioning

confidence: 55%

HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell deathin vitroandin vivo

et al. 2015

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Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin. Treatment with RET specific kinase inhibitor Vandetanib failed to reduce RET phosphorylation and inhibit cell growth, suggesting that other RTKs may phosphorylate RET. A screening pointed out EGFR and ERBB3 as the strongest expressed phosphorylated RTKs in MLS cells. We show that ERBB3 formed nuclear and cytoplasmic complexes with RET and both RTKs were previously reported to form complexes with EGFR. The formation of RTK hetero complexes could explain the observed Vandetanib resistence in MLS. EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death. Treatment of MLS xenograft carrying Nude mice resulted in massive necrosis, rupture of capillaries and hemorrhages in tumor tissues. We conclude that complex formation between RET and other RTKs may cause RTK inhibitor resistance. HSP90 inhibitors can overcome this resistance and are thus promising drugs for treatment of MLS/RCLS.

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“…A strong positive relation was detected between pEGFR and MMP7/13 in gastric cancer 40 . HSP90 inhibition by AUY922 treatment deactivated PI3K/AKT as well as Raf/MAPK/ERK pathways in three liposarcoma cell lines 41 . Furthermore, macrophages stimulate gastric cancer invasion through phosphorylation of EGFR Y1086, c-Src, Erk1/2 and Akt phosphorylation 42 .…”

Section: Discussionmentioning

confidence: 95%

In vitro Cytotoxic Activities of the Oral Platinum(IV) Prodrug Oxoplatin and HSP90 Inhibitor Ganetespib against a Panel of Gastric Cancer Cell Lines

Klameth¹,

Rath²,

Hamilton³

2017

J. Cancer

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Gastric cancer exhibits a poor prognosis and is the third most common cause of cancer death worldwide. Chemotherapy of metastatic gastric cancer is based on combinations of platinum drugs and fluoropyrimidines, with added agents. Oxoplatin is a stable oral platinum(IV) prodrug which is converted to a highly active tetrachlorido(IV) complex under acidic conditions. In the present work, we studied the cytotoxic effects of oxoplatin against a panel of four gastric cancer cell lines in vitro. Furthermore, the role of HSP90 in chemoresistance of these lines was investigated using the specific inhibitor ganetespib. The KATO-III, MKN-1, MKN-28, MKN-45 lines were used in MTT chemosensitivity, cell cycle and apoptosis assays. KATO-III is a signet ring diffuse cell type, MKN-1 an adenosquamous primary, MKN-28 a well-differentiated intestinal type and the MKN-45 a poorly differentiated, diffuse type gastric carcinoma line. Cytotoxicity was tested in MTT assays and intracellular signal transduction with proteome profiler Western blot arrays. Interactions of platinum drugs and ganetespib were calculated with help of the Chou-Talalay method. The prodrug oxoplatin revealed low activity against the four gastric cancer cell lines, whereas the platinum tetrachlorido(IV) complex and cisplatin gave IC50 values of 1-3 µg/ml with increasing chemoresistance observed in the order of MKN-1, KATO-III, MKN-28 to MKN-45. With exception of KATO-III and MKN-28/oxoplatin, all other cell lines featured marked synergistic toxicity with clinically achievable concentrations of ganetespib. Oral administration of a platinum agent such as oxoplatin would be of great value for patients and care providers alike. These results suggest that the oncogene-stabilizing HSP90 chaperone represents an important mediator of chemoresistance in gastric cancer. Ganetespib reduced the phosphorylation of p53, Akt1/2/3 and PRAS40, as well as of WNK1, a kinase which regulates intracellular chloride concentrations. Intracellular chloride was reported to control proliferation of gastric cancer cell lines. Expression of MUC1 was not downregulated in contrast to the expression of CAIX, a prognostic marker in gastric cancer. In conclusion, the HSP90 inhibitor ganetespib synergizes with platinum anticancer drugs and modulates intracellular signal transduction in direction of a less proliferative and aggressive phenotype.

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Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma

Cited by 10 publications

References 32 publications

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell deathin vitroandin vivo

In vitro Cytotoxic Activities of the Oral Platinum(IV) Prodrug Oxoplatin and HSP90 Inhibitor Ganetespib against a Panel of Gastric Cancer Cell Lines

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