作者: Flati, Vincenzo ; Biordi, Leda Assunta ; Festuccia, Claudio ; Kauffman, Michael ; Shacham, Sharon ; Mancini, Andrea ; Marampon, Francesco ; Gravina, Giovanni Luca ; Sferra, Roberta ; Iorio, Roberto ; Landesman, Yosef ; Argueta, Christian ; Colapietro, Alessandro ; Pompili, Simona

BACKGROUND AND AIMS:

Docetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon.

MATERIAL AND METHODS:

Here, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their. DTX resistant derivatives.

RESULTS AND CONCLUSIONS:

We show that DTX resistance may involve overexpression of β-III tubulin (TUBB3) and P-glycoprotein as well as increased cytoplasmic accumulation of Foxo3a. Increased levels of XPO-1 were also observed in DTX resistant cells suggesting that SINE compounds may modulate DTX effectiveness in sensitive cells as well as restore the sensitivity to DTX in resistant ones. Pretreatment with SINE compounds, indeed, sensitized to DTX through increased tumor shrinkage and apoptosis by preventing DTX-induced cell cycle arrest. Basally SINE compounds induce FOXO3a activation and nuclear accumulation increasing the expression of FOXO-responsive genes including p21, p27 and Bim causing cell cycle arrest. SINE compounds-catenin and survivin supporting apoptosis. βdown-regulated Cyclin D1, c-myc, Nuclear sequestration of p-Foxo3a was able to reduce ABCB1 and TUBB3 H2AX levels, prolonged γ expression. Selinexor treatment increased DTX-mediated double strand breaks (DSB), and reduced the levels of DNA repairing proteins including DNA PKc and Topo2A. Our results provide supportive evidence for the therapeutic use of SINE compounds in combination with DTX suggesting their clinical use in mCRPC patients.

2016-12-01·Cancer letters1区 · 医学

Anti-tumor activity of selective inhibitor of nuclear export (SINE) compounds, is enhanced in non-Hodgkin lymphoma through combination with mTOR inhibitor and dexamethasone

1区 · 医学

Article

作者: Aboukameel, Amro ; Carlson, Robert ; Zonder, Jeffrey ; Kauffman, Michael ; Azmi, Asfar S ; Muqbil, Irfana ; Mohammad, Ramzi M ; Baloglu, Erkan ; Bhutani, Divaya ; Senapedis, William ; Elloul, Sivan ; Shacham, Sharon

In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL. Combination of selinexor with DEX or EVER resulted in enhanced cytotoxicity in WSU-DLCL2 and WSU-FSCCL cells which was consistent with enhanced apoptosis. Molecular analysis showed enhancement in the activation of apoptotic signaling and down-regulation of XPO1. This enhancement is consistent with the mechanism of action of these drugs in that both selinexor and DEX antagonize NF-κB (p65) and mTOR (EVER target) is an XPO1 cargo protein. SINE compounds, KPT-251 and KPT-276, showed activities similar to CHOP (cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone) regimen in subcutaneous and disseminated NHL xenograft models in vivo. In both animal models the anti-lymphoma activity of selinexor is enhanced through combination with DEX or EVER. The in vivo activity of selinexor and related SINE compounds relative to 'standard of care' treatment is consistent with the objective responses observed in Phase I NHL patients treated with selinexor. Our pre-clinical data provide a rational basis for testing these combinations in Phase II NHL trials.

2015-12-01·BMC cancer2区 · 医学

Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds

2区 · 医学

ArticleOA

作者: Klebanov, Boris ; Kashyap, Trinayan ; Kalid, Ori ; Shechter, Sharon ; Landesman, Yosef ; Saint-Martin, Jean-Richard ; Crochiere, Marsha ; Senapedis, William

BACKGROUND:

Exportin 1 (XPO1) is a well-characterized nuclear export protein whose expression is up-regulated in many types of cancers and functions to transport key tumor suppressor proteins (TSPs) from the nucleus. Karyopharm Therapeutics has developed a series of small-molecule Selective Inhibitor of Nuclear Export (SINE) compounds, which have been shown to block XPO1 function both in vitro and in vivo. The drug candidate, selinexor (KPT-330), is currently in Phase-II/IIb clinical trials for treatment of both hematologic and solid tumors. The present study sought to decipher the mechanisms that render cells either sensitive or resistant to treatment with SINE compounds, represented by KPT-185, an early analogue of KPT-330.

METHODS:

Using the human fibrosarcoma HT1080 cell line, resistance to SINE was acquired over a period of 10 months of constant incubation with increasing concentration of KPT-185. Cell viability was assayed by MTT. Immunofluorescence was used to compare nuclear export of TSPs. Fluorescence activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), and immunoblots were used to measure effects on cell cycle, gene expression, and cell death. RNA from naïve and drug treated parental and resistant cells was analyzed by Affymetrix microarrays.

RESULTS:

Treatment of HT1080 cells with gradually increasing concentrations of SINE resulted in >100 fold decrease in sensitivity to SINE cytotoxicity. Resistant cells displayed prolonged cell cycle, reduced nuclear accumulation of TSPs, and similar changes in protein expression compared to parental cells, however the magnitude of the protein expression changes were more significant in parental cells. Microarray analyses comparing parental to resistant cells indicate that a number of key signaling pathways were altered in resistant cells including expression changes in genes involved in adhesion, apoptosis, and inflammation. While the patterns of changes in transcription following drug treatment are similar in parental and resistant cells, the extent of response was more robust in the parental cells.

CONCLUSIONS:

These results suggest that SINE resistance is conferred by alterations in signaling pathways downstream of XPO1 inhibition. Modulation of these pathways could potentially overcome the resistance to nuclear export inhibitors.

项与 KPT-251 相关的新闻（医药）

2025-08-11

·药事纵横

全球首个！XPO1抑制剂方案落地中国，开启靶向治疗新纪元

在癌症治疗领域，每一次新药物的突破都如同黑暗中的曙光，为患者带来新的希望。2025年7月28日，德琪医药宣布，塞利尼索片的新适应症正式获得中国国家药品监督管理局（NMPA）批准，与硼替佐米和地塞米松联用（XVD方案），适用于既往接受过至少一线治疗的多发性骨髓瘤（MM）成人患者。这一获批不仅是塞利尼索在中国获批的第3项适应症，更是全球首个XPO1抑制剂在多发性骨髓瘤治疗领域的重要进展，为患者带来了全新的治疗选择和希望。 (一)XPO1抑制剂的发现与作用机制 1.1 XPO1抑制剂的发现历程 l 早期探索：20世纪90年代，Nishi等人发现了第一个特异的XPO1抑制剂——leptomycin B。它是一种抗生素，能与XPO1的半胱氨酸528残基（Cys528）共价结合，是XPO1与核输出信号（NES）相互作用的不可逆抑制剂。但由于其对XPO1的强特异性，在治疗难治性癌症患者的I期试验中，因出现严重的全身毒性，如恶心、呕吐、厌食等而终止。 l 后续发展：在leptomycin B和相关化合物早期失败后，研究人员采用基于共识诱导匹配对接（CIFD）结构的药物开发方法，开发出一类新的小分子XPO1抑制剂，被称为核出口选择性抑制剂（SINE）化合物，包括KPT-185、KPT-251、KPT-276、塞利尼索（Selinexor）、eltanexor和verdinexor等。这些抑制剂在XPO1的NES结合袋中与Cys528共价相互作用，是缓慢可逆的抑制剂，在活体中具有更好的耐受性。 1.2 XPO1抑制剂的作用机制 l XPO1的正常功能：XPO1，也称为染色体区域维持蛋白1，是核输出蛋白家族中的一员，主要负责将细胞核内的蛋白质和部分细胞核RNA转运到细胞质。在细胞核中，染色体凝聚调控因子1（RCC1）与染色质相互作用，导致RanGTP水平增加。RanGTP与XPO1结合，使XPO1的NES结合位点打开，货物蛋白富含亮氨酸的NES结构域结合在XPO1的疏水性槽内，形成稳定的三元复合物，然后与核孔复合物结合，将货物蛋白输出到细胞质。 l XPO1在疾病中的异常：在多种癌症中，XPO1常常过度表达。XPO1过表达会导致肿瘤抑制蛋白如p53、p73、Foxo1等的核输出增加，使这些肿瘤抑制蛋白在细胞核内的浓度降低，无法发挥正常的抑制肿瘤生长和促进细胞凋亡的作用，从而促进肿瘤细胞的生长和存活。此外，XPO1还参与了多种生长调节蛋白和抗凋亡蛋白的出核转运，进一步推动肿瘤的发展。 l XPO1抑制剂的作用：XPO1抑制剂通过与XPO1的Cys528残基共价结合，阻断XPO1与RanGTP的相互作用，从而抑制XPO1介导的核输出过程。这使得肿瘤抑制蛋白在细胞核内积累，重新启动并放大它们的肿瘤抑制功能，导致癌细胞选择性凋亡，同时不会对正常细胞造成显著影响。例如，塞利尼索作为全球第一款获批的核输出抑制剂，通过结合并抑制XPO1发挥作用，已获批用于治疗复发/难治性多发性骨髓瘤、复发/难治性弥漫性大B细胞淋巴瘤等。 XPO1抑制剂的作用机制示意图 (二)XPO1抑制剂的临床试验与研究 2.1 多发性骨髓瘤 l STORM试验：这是一项多中心、单臂、国际临床2b期研究，入组122例既往接受过多线治疗并且对5种不同疗法耐药的难治多发性骨髓瘤患者，患者接受塞利尼索联合低剂量地塞米松进行治疗。结果显示，总缓解率（ORR）达到26.2%，其中有2例患者达到严格意义的完全缓解（SCR），30例患者达到部分缓解及以上，患者的平均缓解时间为4.4个月。 l BOSTON Ⅲ期研究：对塞利尼索联合硼替佐米和地塞米松（XVD）方案和VD方案在经既往治疗的多发性骨髓瘤患者中的有效性进行了评估。研究结果表明，XVD治疗与VD治疗相比，深度缓解（定义为≥VGPR）的比率显著更高（44.6% vs. 32.4%），中位无进展生存期（PFS）显著延长（13.93个月 vs 9.46个月），且中位缓解持续时间更长（20.3个月 vs 12.9个月）。此外，XVD组中有17%的患者出现CR或SCR，而VD治疗组仅有10%。且XVD组周围神经病变（PN）的发生率显著低于VD组（32% vs. 47%）。 2.2 弥漫大B细胞淋巴瘤 l SADAL试验：是一项多中心、单臂的IIb期临床研究，共入组267例既往至少接受过2线治疗的复发难治弥漫大B细胞淋巴瘤患者。研究结果显示，在127例患者中，单药口服塞利尼索的总缓解率（ORR）为29%，完全缓解（CR）率为13%。在获得PR或CR的39例患者中，38%的患者缓解持续时间至少为6个月，15%的患者缓解持续时间至少为12个月。 l 中山大学肿瘤防治中心研究：回顾性分析16例接受塞利尼索联合化疗或非化疗方案一线治疗的老年弥漫大B细胞淋巴瘤患者（中位年龄70.5岁），结果显示客观缓解率（ORR）达93.8%，完全缓解（CR）率81.3%，1年无进展生存（PFS）率79.6%。化疗非依赖方案（如R2、R-O）的CR率为100%。血液学毒性常见但可控，非血液学不良反应以轻度为主。 2.3 急性髓系白血病 l 塞利尼索作为一种核输出蛋白1（XPO-1）抑制剂，通过激活肿瘤抑制蛋白诱导癌细胞凋亡，在复发难治性急性髓系白血病（AML）中显示出治疗潜力。基于SAIL研究，塞利尼索联合化疗方案（60mg，每周2次）可使患者总体缓解率达50%，中位总生存期为8.2个月。该研究初步总结了实现完全缓解患者的分子生物学特征，并重点报道了一例复发性AML患者通过长期塞利尼索维持治疗获得良好疗效与耐受性的案例，为该疗法的临床应用提供了新证据。塞利尼索维持治疗实现CR/CRi相关的基因频率统计柱状图 2.4 其他癌症 l 基底型乳腺癌：昆明医科大学生物医学工程研究院的陈策实研究员团队发现KLF5可通过诱导XPO1基因转录促进基底型乳腺癌细胞增殖，XPO1也通过增加FOXO1的mRNA核输出，进而增加KLF5的表达，形成正反馈调节回路。研究表明XPO1抑制剂KPT-330和CDK4/6抑制剂Palbociclib联合使用可有效抑制基底型乳腺癌细胞增殖和肿瘤生长，为基底型乳腺癌患者的临床治疗提供了一种新的联合用药策略。 l 非小细胞肺癌：2025年2月，《Clinical Cancer Research》公布了口服XPO1抑制剂塞利尼索联合多西他赛治疗先前治疗过的晚期KRAS突变非小细胞肺癌患者的I/II期临床试验结果。在32例可评估疗效的患者中，7例（22%）部分缓解（PR），18例（56%）病情稳定（SD）。结果与KRAS突变类型无关，但在TP53野生型病例中的结果明显更好，反应率为27% vs 9%，疾病控制率（DCR）为80% vs 27%，中位PFS为7.4个月vs 1.8个月。此外，G12C突变和和非G12C突变患者的中位OS分别为6.5个月和7.5个月；P53突变和非突变患者的中位OS分别为5.8个月和15.7个月。 PFS和OS结果 (三)总结目前XPO1抑制剂在血液系统肿瘤和实体瘤中的应用已取得一定成果，未来有望进一步拓展到其他类型的肿瘤，如骨髓纤维化、T细胞淋巴瘤和NK细胞淋巴瘤等。在新型抑制剂开发方面，除了塞利尼索等已上市的XPO1抑制剂，还有许多新型XPO1抑制剂处于临床试验阶段，如eltanexor、verdinexor等。这些新型抑制剂在药代动力学、毒性和有效性方面可能具有更好的表现，为患者提供更多的治疗选择。与此同时，为了更好地指导临床用药，还需要进一步探索XPO1抑制剂的生物标志物，以识别可能对XPO1抑制剂治疗敏感的患者，提高治疗的精准性。参考文献： [1] Klement P, Fiedler W, Gabdoulline R, Dallmann LK, Wienecke CP, Schiller J, Kandziora C, Teich K, Heida B, Büttner K, Brandes M, Funke C, Wichmann M, Othman B, Chromik J, Amberg S, Kebenko M, Schlipfenbacher V, Wilke AC, Modemann F, Janning M, Serve H, Bokemeyer C, Theile S, Deppermann U, Kranich AL, Ganser A, Thol F, Heuser M. Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy. Ann Hematol. 2023 Feb;102(2):323-328. doi: 10.1007/s00277-022-05075-4. [2] Uddin MH, Al-Hallak MN, Khan HY, Aboukameel A, Li Y, Bannoura SF, Dyson G, Kim S, Mzannar Y, Azar I, Odisho T, Mohamed A, Landesman Y, Kim S, Beydoun R, Mohammad RM, Philip PA, Shields AF, Azmi AS. Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model. Clin Transl Med. 2023 Dec;13(12):e1513. doi: 10.1002/ctm2.1513. [3] von Itzstein MS, Burns TF, Dowell JE, Horn L, Camidge DR, York SJ, Eaton KD, Kyle K, Fattah F, Liu J, Mu-Mosley H, Gupta A, Nadeem U, Gao A, Zhang S, Gerber DE. Phase I/II Trial of Exportin 1 Inhibitor Selinexor plus Docetaxel in Previously Treated, Advanced KRAS-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2025 Feb 17;31(4):639-648. doi: 10.1158/1078-0432.CCR-24-1722. 作者介绍：Ketty，主要从事药物研发和科普，制药行业政策和发展研究工作。药事纵横投稿须知：稿费已上调，欢迎投稿

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适应症	最高研发状态	国家/地区	公司	日期
前列腺癌	临床前	美国	Karyopharm Therapeutics, Inc.	2015-12-01
前列腺癌	临床前	意大利	University of L'Aquila	2015-12-01
急性髓性白血病	临床前	美国	Karyopharm Therapeutics, Inc.	2012-07-31