核输出蛋白1抑制剂的抗肿瘤作用及联合用药策略研究进展

Research progress on the antitumor effects of nuclear export protein 1 inhibitors and combined medication strategies

摘要

核输出蛋白 1（exportin 1，XPO1）在多种恶性肿瘤中异常高表达，可通过介导 p53、RB1、FOXO 等重要抑癌蛋白的核输出导致其丧失抗肿瘤作用。XPO1 抑制剂塞利尼索虽已进入临床应用，但其单药抗肿瘤效果仍有待提升，这与 XPO1 抑制剂的干预受到多条信号通路的交叉调控密切相关。本文从 XPO1 在肿瘤细胞中的核心调控功能出发，系统总结了 XPO1 抑制剂与多种靶点抑制剂的联用研究现状，包括周期蛋白依赖性激酶 4/6（CDK4/6）、FMS 样酪氨酸激酶 3（FLT3）、溴结构域蛋白（BET）、共济失调毛细血管扩张症和 Rad3 相关蛋白（ATR）、B 细胞淋巴瘤-2/小鼠双微体扩增基因 2（BCL2/MDM2）抑制剂等，旨在为以 XPO1 为核心的联合治疗策略提供参考。

Abstract

Exportin 1 (XPO1) is aberrantly overexpressed in various malignant tumors and can lead to the loss of anti-tumor effects of important tumor suppressor proteins such as p53, RB1, and FOXO by mediating their nuclear export. Although XPO1 inhibitor Selinexor has entered clinical application, its single-agent anti-tumor activity remains suboptimal, which is closely related to the compensatory activation of multiple signaling pathways in response to XPO1 inhibition. Focusing on the core regulatory role of XPO1 in tumor cells, this article systematically summarizes the current landscape of combination therapies involving XPO1 inhibitors and various targeted agents, including inhibitors of CDK4/6, FLT3, BET, ATR, and BCL2/MDM2, aiming to provide some reference for the development of XPO1-centered combination therapy strategies.

关键词

XPO1 / 耐药机制 / 联合治疗 / 肿瘤信号通路

Key words

XPO1 / drug resistance mechanism / combination therapy / tumor signaling pathway

参考文献

[1] Azmi AS, Uddin MH, Mohammad RM. The nuclear export protein XPO1: from biology to targeted therapy[J]. Nat Rev Clin Oncol, 2021, 18(3): 152-169.

[2] Chaudhry S, Beckedorff F, Jasdanwala SS, et al. Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition[J]. Leukemia, 2024, 38(9): 1894-1905.

[3] Kasamon YL, Price LSL, Okusanya OO, et al. FDA approval summary: selinexor for relapsed or refractory diffuse large—B—cell lymphoma[J]. Oncologist, 2021, 26(10): 879-886.

[4] Garzon R, Savona M, Baz R, et al. A phase 1 clinical trial of single—agent selinexor in acute myeloid leukemia[J]. Blood, 2017, 129(24): 3165-3174.

[5] Mateos MV, Gavriatopoulou M, Facon T, et al. Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma[J]. J Hematol Oncol, 2021, 14(1): 59.

[6] Liu XL, Wang BB, Wang Y, et al. Unbiased screening reveals that blocking exportin 1 overcomes resistance to PI3Kα inhibition in breast cancer[J]. Signal Transduct Target Ther, 2019, 4: 49.

[7] Saenz—Ponce N, Pillay R, de Long LM, et al. Targeting the XPO1—dependent nuclear export of E2F7 reverses anthracycline resistance in head and neck squamous cell carcinomas[J]. Sci Transl Med, 2018, 10(447): eaar7223.

[8] Li K, Mo CF, Gong D, et al. DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non—small cell lung cancer cells via activation of β—catenin[J]. Cancer Lett, 2017, 400: 194-202.

[9] Zhang J, Gu Y, Guan JH, et al. Clinical significance of XPO1 high expression in diffuse large B—cell lymphoma and its mechanism[J]. J Exp Hematol (中国实验血液学杂志), 2025, 33(2): 393—406.

[10] Hilton LK, Collinge B, Ben—Neriah S, et al. Motive and opportunity: MYC rearrangements in high—grade B—cell lymphoma with MYC and BCL2 rearrangements (an LLMPP study)[J]. Blood, 2024, 144(5): 525-540.

[11] Trkulja KL, Manji F, Kuruvilla J, et al. Nuclear export in non—Hodgkin lymphoma and implications for targeted XPO1 inhibitors[J]. Biomolecules, 2023, 13(1): 111.

[12] Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B—cell lymphoma (SADAL): a single—arm, multinational, multicentre, open—label, phase 2 trial[J]. Lancet Haematol, 2020, 7(7): e511-e522.

[13] Deng MM, Zhang MZ, Xu—Monette ZY, et al. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53[J]. J Hematol Oncol, 2020, 13(1): 148.

[14] Kotlov N, Bagaev A, Revuelta MV, et al. Clinical and biological subtypes of B—cell lymphoma revealed by microenvironmental signatures[J]. Cancer Discov, 2021, 11(6): 1468-1489.

[15] Shimosato Y, Yamamoto K, Jia YH, et al. NPM1—fusion proteins promote myeloid leukemogenesis through XPO1—dependent HOX activation[J]. Leukemia, 2025, 39(1): 75-86.

[16] Pianigiani G, Gagliardi A, Mezzasoma F, et al. Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1—mutated AML[J]. Blood Adv, 2022, 6(22): 5938-5949.

[17] Zhang WG, Ly C, Ishizawa J, et al. Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti—leukemia effects through induction of differentiation and apoptosis in FLT3—mutated acute myeloid leukemias: from concept to clinical trial[J]. Haematologica, 2018, 103(10): 1642-1653.

[18] Coutinho DF, Mundi PS, Marks LJ, et al. Validation of a non—oncogene encoded vulnerability to exportin 1 inhibition in pediatric renal tumors[J]. Med, 2022, 3(11): 774-791. e7.

[19] Wang ZB, Pan BL, Yao YX, et al. XPO1 intensifies sorafenib resistance by stabilizing acetylation of NPM1 and enhancing epithelial—mesenchymal transition in hepatocellular carcinoma[J]. Biomed Pharmacother, 2023, 160: 114402.

[20] Uddin MH, Al—Hallak MN, Khan HY, et al. Molecular analysis of XPO1 inhibitor and gemcitabine—nab—paclitaxel combination in KPC pancreatic cancer mouse model[J]. Clin Transl Med, 2023, 13(12): e1513.

[21] Wang H, Yuan SX, Zheng Q, et al. Dual inhibition of CDK4/6 and XPO1 induces senescence with acquired vulnerability to CRBN—based PROTAC drugs[J]. Gastroenterology, 2024, 166(6): 1130-1144. e8.

[22] Evans AE, Afroz S, Magstadt A, et al. The XPO1 inhibitor eltanexor modulates the Wnt/β—catenin signaling pathway to reduce colorectal cancer tumorigenesis[J]. Cancer Res Commun, 2025, 5(7): 1140-1154.

[23] Wang YL, Chen JF, Gao Y, et al. CDK4/6 inhibition augments anti—tumor efficacy of XPO1 inhibitor selinexor in natural killer/T—cell lymphoma[J]. Cancer Lett, 2024, 597: 217080.

[24] Nishida Y, Ishizawa J, Ayoub E, et al. Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias[J]. Sci Adv, 2023, 9(48): eadh1436.

[25] Wang PH, Hu CH, Fan JQ, et al. Innovative evaluation of selinexor and JQ1 synergy in leukemia therapy via C—MYC inhibition[J]. J Transl Med, 2025, 23(1): 520.

[26] Tang Y, Liu R, Zhu J, et al. Positive feedback regulation between KLF5 and XPO1 promotes cell cycle progression of basal like breast cancer[J]. Adv Sci, 2025, 12(16): 2412096.

[27] Carter BZ, Mak PY, Ayoub E, et al. Restoring p53 wild—type conformation in TP53—Y220C—mutant acute myeloid leukemia[J]. Blood, 2025, 146(21): 2574-2588.

[28] Inoue A, Robinson FS, Minelli R, et al. Sequential administration of XPO1 and ATR inhibitors enhances therapeutic response in TP53—mutated colorectal cancer[J]. Gastroenterology, 2021, 161(1): 196-210.

[29] Fassl A, Geng Y, Sicinski P. CDK4 and CDK6 kinases: From basic science to cancer therapy[J]. Science, 2022, 375(6577): eabc1495.

[30] Dick FA, Rubin SM. Molecular mechanisms underlying RB protein function[J]. Nat Rev Mol Cell Biol, 2013, 14(5): 297-306.

[31] Luo QY, Wu XW, Chang W, et al. ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c—Myc—mediated cancer stemness[J]. Cell Death Differ, 2020, 27(6): 1981-1997.

[32] Grob T, Sanders MA, Vonk CM, et al. Prognostic value of FLT3—internal tandem duplication residual disease in acute myeloid leukemia[J]. J Clin Oncol, 2023, 41(4): 756-765.

[33] Romero D. Responses to selinexor in multiple myeloma[J]. Nat Rev Clin Oncol, 2019, 16(11): 661.

[34] Deutzmann A, Sullivan DK, Dhanasekaran R, et al. Nuclear to cytoplasmic transport is a druggable dependency in MYC—driven hepatocellular carcinoma[J]. Nat Commun, 2024, 15: 963.

[35] Luo Q, Meng R. Initial exploration of the BET inhibitor RO6870810 in the treatment of solid tumors and lymphomas[J]. J Evid Based Med (循证医学), 2024, 24(5): 284—289,320.

[36] Zhu XF, Liu W, Tang XC, et al. The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS—STING in response to light damage[J]. J Neuroinflammation, 2023, 20(1): 119.

[37] Ou L, Wang XY, Cheng SM, et al. Verdinexor, a selective inhibitor of nuclear exportin 1, inhibits the proliferation and migration of esophageal cancer via XPO1/c—myc/FOSL1 axis[J]. Int J Biol Sci, 2022, 18(1): 276-291.

[38] Fiskus W, Piel J, Collins M, et al. BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor[J]. Blood, 2024, 143(20): 2059-2072.

[39] Fiskus W, Mill CP, Birdwell C, et al. Targeting of epigenetic co—dependencies enhances anti—AML efficacy of Menin inhibitor in AML with MLL1—r or mutant NPM1[J]. Blood Cancer J, 2023, 13: 53.

[40] Zeng JK, Hills SA, Ozono E, et al. Cyclin E—induced replicative stress drives p53—dependent whole—genome duplication[J]. Cell, 2023, 186(3): 528-542. e14.

[41] Liu JY, Li SR, Wang Q, et al. Sonrotoclax overcomes BCL2 G101V mutation—induced venetoclax resistance in preclinical models of hematologic malignancy[J]. Blood, 2024, 143(18): 1825-1836.

[42] Kwon JW, Oh JS, Seok SH, et al. Combined inhibition of Bcl—2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency[J]. Mol Cancer, 2023, 22(1): 156.

[43] Bhatt S, Pioso MS, Olesinski EA, et al. Reduced mitochondrial apoptotic priming drives resistance to BH3 mimetics in acute myeloid leukemia[J]. Cancer Cell, 2020, 38(6): 872-890. e6.

[44] Liu JX, Wei LY, Miao Q, et al. MDM2 drives resistance to Osimertinib by contextually disrupting FBW7—mediated destruction of MCL—1 protein in EGFR mutant NSCLC[J]. J Exp Clin Cancer Res, 2024, 43(1): 302.

[45] Luedtke DA, Su YW, Liu S, et al. Inhibition of XPO1 enhances cell death induced by ABT—199 in acute myeloid leukaemia via Mcl—1[J]. J Cell Mol Med, 2018, 22(12): 6099-6111.

[46] Alhalabi O, Gouda MA, Milton DR, et al. A phase IB trial of selinexor in combination with immune checkpoint blockade in patients with advanced renal cell carcinoma[J]. Cancer Med, 2025, 14(4): e70280.

[47] Khouri J, Sborov D, Rossi A, et al. Focusing on selinexor for holding and bridging prior to CAR—T in relapsed/refractory multiple myeloma[J]. J Clin Med, 2025, 14(12): 4071.

[48] Syed YY. Selinexor: first global approval[J]. Drugs, 2019, 79(13): 1485-1494.

[49] Hing ZA, Fung HYJ, Ranganathan P, et al. Next generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematologic malignancies[J]. Blood, 2015, 126(23): 317.

[50] Pan LJ, Cheng C, Duan PW, et al. XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor[J]. J Exp Clin Cancer Res, 2021, 40(1): 255.

[51] Gravina GL, Senapedis W, McCauley D, et al. Nucleo—cytoplasmic transport as a therapeutic target of cancer[J]. J Hematol Oncol, 2014, 7: 85.

[52] Cornell RF, Baz R, Richter JR, et al. A phase 1 clinical trial of oral eltanexor in patients with relapsed or refractory multiple myeloma[J]. Am J Hematol, 2022, 97(2): E54-E58.

[53] Lee S, Mohan S, Knupp J, et al. Oral eltanexor treatment of patients with higher—risk myelodysplastic syndrome refractory to hypomethylating agents[J]. J Hematol Oncol, 2022, 15(1): 103.

[54] Jorquera PA, Mathew C, Pickens J, et al. Verdinexor (KPT—335), a selective inhibitor of nuclear export, reduces respiratory syncytial virus replication in vitro[J]. J Virol, 2019, 93(4): e01684-e01618.

基金资助

浙江省“尖兵领雁+X”科技计划项目(2025C02064)

国家自然科学基金项目(82470179)