Vannas Christoffer, Andersson Lisa, Dolatabadi Soheila, Ranji Parmida, Lindén Malin, Jonasson Emma, Ståhlberg Anders, Fagman Henrik, Åman Pierre
Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
Department of Oncology, Sahlgrenska University Hospital, SE-413 46 Gothenburg, Sweden.
Biomedicines. 2022 Mar 7;10(3):624. doi: 10.3390/biomedicines10030624.
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.
复发或转移性黏液样脂肪肉瘤（MLS）患者的治疗选择仍然有限，目前尚无靶向治疗方法。有人提出抑制伴侣蛋白HSP90家族可能是MLS患者的一种治疗选择。然而，不同HSP90抑制剂的临床效果差异很大，且尚未在MLS中进行比较研究。在此，我们评估了HSP90抑制剂17-DMAG、AUY922和STA-9090对MLS细胞系以及MLS患者来源的异种移植（PDX）模型的影响。尽管所有药物均抑制了MLS细胞系的体外生长，但体内反应却不一致。17-DMAG抑制肿瘤生长，而AUY922却出人意料地导致肿瘤生长增加和更具侵袭性的形态学表型。在体外，17-DMAG和STA-9090降低了MAPK和PI3K/AKT信号通路的活性，而AUY922导致下游ERK的代偿性上调。此外，所有三种测试的HSP90抑制剂与曲贝替定均显示出协同联合效应，但与多柔比星则无此效应。总之，我们的结果表明，不同的HSP90抑制剂尽管具有相同的靶点，但其下游效应和治疗结果可能存在显著差异。在针对MLS或其他恶性肿瘤开展临床试验之前，应考虑这些结果。
