The therapeutic options for patients with relapsed or metastatic
myxoid liposarcoma (MLS) remain scarce and there is currently no targeted
therapy available. Inhibition of the HSP90 family of chaperones has been suggested as a possible therapeutic option for patients with MLS. However, the clinical effect of different HSP90 inhibitors vary considerably and no comparative study in MLS has been performed. Here, we evaluated the effects of the HSP90 inhibitors
17-DMAG,
AUY922 and
STA-9090 on MLS cell lines and in an MLS patient-derived xenograft (PDX) model. Albeit all drugs inhibited in vitro growth of MLS cell lines, the in vivo responses were discrepant. Whereas
17-DMAG inhibited
tumor growth,
AUY922 surprisingly led to increased
tumor growth and a more aggressive morphological phenotype. In vitro,
17-DMAG and
STA-9090 reduced the activity of the MAPK and PI3K/AKT signaling pathways, whereas
AUY922 led to a compensatory upregulation of downstream ERK. Furthermore, all three tested HSP90 inhibitors displayed a synergistic combination effect with trabectidin, but not with
doxorubicin. In conclusion, our results indicate that different HSP90 inhibitors, albeit having the same target, can vary significantly in downstream effects and treatment outcomes. These results should be considered before proceeding into clinical trials against MLS or other
malignancies.