Zuco Valentina, Pasquali Sandro, Tortoreto Monica, Brich Silvia, Percio Stefano, Dagrada Gian Paolo, Colombo Chiara, Sanfilippo Roberta, Lauricella Calogero, Gounder Mrinal, El Bezawy Rihan, Barisella Marta, Dei Tos Angelo Paolo, Casali Paolo Giovanni, Gronchi Alessandro, Stacchiotti Silvia, Zaffaroni Nadia
Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133, Milan, Italy.
Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133, Milan, Italy.
J Exp Clin Cancer Res. 2021 Mar 1;40(1):83. doi: 10.1186/s13046-021-01886-x.
Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of wild-type p53. MDM2 ubiquitination of p53 facilitates its XPO1-mediated nuclear export, thus limiting p53 tumor suppressor functions. Consequently, nuclear export is a rational target in DDLPS. We directly compared the antitumor activity of the first-in class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy in sarcomas, in DDLPS patient-derived xenografts (PDXs) and primary cell lines.
Drug activity was assessed in three PDXs (and two corresponding cell lines) established from the dedifferentiated component of primary untreated retroperitoneal DDLPS with myogenic (N = 2) and rhabdomyoblastic (N = 1) differentiation from patients who underwent surgery. These models were marked by amplification of MDM2, CDK4 and HMGA2 genes.
Selinexor was moderately active in the three PDXs but achieved greater tumor response compared to doxorubicin (maximum tumor volume inhibition: 46-80 % vs. 37-60 %). The PDX harboring rhabdomyoblastic dedifferentiation showed the highest sensitivity to both agents. PDX response to selinexor and doxorubicin was not associated with the extent of MDM2 and CDK4 gene amplification. Interestingly, the most chemosensitive PDX model showed the lowest extent of HMGA2 amplification. Selinexor was also more efficient than doxorubicinin in inducing an apoptotic response in PDXs and cell lines. Consistently, an increased nuclear accumulation of p53 was seen in all selinexor-treated models. In addition, a time-dependent decrease of survivin expression, with an almost complete abrogation of the cytoplasmic anti-apoptotic pool of this protein, was observed as a consequence of the decreased acetylation/activation of STAT3 and the increased ubiquitination of nuclear survivin.
Selinexor showed a moderate antitumor activity in three DDLPS PDXs, which was, however, consistently higher than doxorubicin across all different models regardless the extent of MDM2 amplification and the histological differentiation. The depletion of survivin protein seems to significantly contribute to the induction of apoptosis through which selinexor exerts its antitumor activity.
去分化脂肪肉瘤（DDLPS）是一种缺乏有效治疗策略且预后较差的肿瘤，在野生型p53存在的情况下表达扩增的MDM2。MDM2对p53的泛素化促进了其XPO1介导的核输出，从而限制了p53的肿瘤抑制功能。因此，核输出是DDLPS的一个合理靶点。我们在DDLPS患者来源的异种移植瘤（PDX）和原代细胞系中，直接比较了一流的XPO1抑制剂塞利尼索和多柔比星（肉瘤的标准一线治疗药物）的抗肿瘤活性。
从接受手术的患者原发性未经治疗的腹膜后DDLPS的去分化成分中建立了三个PDX（以及两个相应的细胞系），其具有肌源性（N = 2）和横纹肌母细胞性（N = 1）分化。这些模型的特点是MDM2、CDK4和HMGA2基因扩增。
塞利尼索在三个PDX中具有中等活性，但与多柔比星相比，实现了更大的肿瘤反应（最大肿瘤体积抑制率：46 - 80%对37 - 60%）。具有横纹肌母细胞去分化的PDX对两种药物表现出最高的敏感性。PDX对塞利尼索和多柔比星的反应与MDM2和CDK4基因扩增程度无关。有趣的是，对化疗最敏感的PDX模型显示HMGA2扩增程度最低。塞利尼索在诱导PDX和细胞系的凋亡反应方面也比多柔比星更有效。一致地，在所有接受塞利尼索治疗的模型中都观察到p53核积累增加。此外，由于STAT3的乙酰化/激活减少和核生存素的泛素化增加，观察到生存素表达随时间下降，该蛋白的细胞质抗凋亡池几乎完全消除。
塞利尼索在三个DDLPS PDX中显示出中等抗肿瘤活性，然而，无论MDM2扩增程度和组织学分化如何，在所有不同模型中其活性始终高于多柔比星。生存素蛋白的消耗似乎显著促进了凋亡的诱导，塞利尼索通过这种方式发挥其抗肿瘤活性。
