Targeting guanine nucleotide exchange factors for novel cancer drug discovery

References

• Wennerberg K, Rossman KL, Der CJ. The ras superfamily at a glance. J Cell Sci. 2005;118(5):843–846. doi: 10.1242/jcs.01660
   PubMed Web of Science ®Google Scholar
• Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129(5):865–877. doi: 10.1016/j.cell.2007.05.018
   PubMed Web of Science ®Google Scholar
• Vetter IR, Wittinghofer A. The guanine nucleotide-binding switch in three dimensions. Science. 2001;294(5545):1299–1304. doi: 10.1126/science.1062023
   PubMed Web of Science ®Google Scholar
• Renault L, Guibert B, Cherfils J. Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor. Nature. 2003;426(6966):525–530. doi: 10.1038/nature02197
   PubMed Web of Science ®Google Scholar
• Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature. 1991;349(6305):117–127. doi: 10.1038/349117a0
   PubMed Web of Science ®Google Scholar
• Vigil D, Cherfils J, Rossman KL, et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer. 2010;10(12):842–857. doi: 10.1038/nrc2960
   PubMed Web of Science ®Google Scholar
• Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, et al. The structural basis of the activation of ras by sos. Nature. 1998;394(6691):337–343. doi: 10.1038/28548
   PubMed Web of Science ®Google Scholar
• Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged? nature reviews drug discovery. Nat Rev Drug Discov. 2020;19(8):533–552. doi: 10.1038/s41573-020-0068-6
   PubMed Web of Science ®Google Scholar
• Swanson KD, Winter JM, Reis M, et al. SOS1 mutations are rare in human malignancies: implications for Noonan syndrome patients. Genes Chromosomes Cancer. 2008;47(3):253–259. doi: 10.1002/gcc.20527
   PubMed Web of Science ®Google Scholar
• Baltanás FC, Zarich N, Rojas-Cabañeros JM, et al. SOS GEFs in health and disease. Biochimica Et Biophysica Acta (BBA) – Reviews On Cancer. 2020;1874(2):188445. doi: 10.1016/j.bbcan.2020.188445
   PubMed Web of Science ®Google Scholar
• Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321–337.e310. doi: 10.1016/j.cell.2018.03.035
   PubMed Web of Science ®Google Scholar
• Cai D, Choi PS, Gelbard M, et al. Identification and characterization of oncogenic SOS1 mutations in lung adenocarcinoma. Mol Cancer Res. 2019;17(4):1002–1012. doi: 10.1158/1541-7786.MCR-18-0316
   PubMed Web of Science ®Google Scholar
• Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol. 2018;15(11):709–720. doi: 10.1038/s41571-018-0105-0
   PubMed Web of Science ®Google Scholar
• Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22. doi: 10.1038/nrc969
   PubMed Web of Science ®Google Scholar
• Margarit SM, Sondermann H, Hall BE, et al. Structural evidence for feedback activation by Ras·GTP of the Ras-specific nucleotide exchange factor SOS. Cell. 2003;112(5):685–695. doi: 10.1016/S0092-8674(03)00149-1
   PubMed Web of Science ®Google Scholar
• Rojas JM, Oliva JL, Santos E. Mammalian son of sevenless guanine nucleotide exchange factors: old concepts and new perspectives. Genes Cancer. 2011;2(3):298–305. doi: 10.1177/1947601911408078
   PubMedGoogle Scholar
• Jeng H-H, Taylor LJ, Bar-Sagi D. Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis. Nat Commun. 2012;3(1):1168. doi: 10.1038/ncomms2173.
   PubMedGoogle Scholar
• Depeille P, Henricks LM, van de Ven RAH, et al. RasGRP1 opposes proliferative EGFR–SOS1–Ras signals and restricts intestinal epithelial cell growth. Nat Cell Biol. 2015;17(6):804–815. doi: 10.1038/ncb3175
   PubMed Web of Science ®Google Scholar
• You X, Kong G, Ranheim EA, et al. Unique dependence on Sos1 in Kras (G12D) -induced leukemogenesis. Blood. 2018;132(24):2575–2579. doi: 10.1182/blood-2018-09-874107
   PubMed Web of Science ®Google Scholar
• Gómez C, Garcia-Navas R, Baltanás FC, et al. Critical requirement of SOS1 for development of BCR/ABL-Driven chronic myelogenous leukemia. Cancers (Basel). 2022;14(16):3893. doi: 10.3390/cancers14163893
   PubMed Web of Science ®Google Scholar
• Hofmann MH, Gmachl M, Ramharter J, et al. BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discov. 2021;11(1):142–157. doi: 10.1158/2159-8290.CD-20-0142
   PubMed Web of Science ®Google Scholar
• Ketcham JM, Haling J, Khare S, et al. Design and Discovery of MRTX0902, a potent, selective, brain-penetrant, and orally bioavailable inhibitor of the SOS1: KRAS protein-protein interaction. J Med Chem. 2022;65(14):9678–9690. doi: 10.1021/acs.jmedchem.2c00741
   PubMedGoogle Scholar
• Sudhakar N, Yan L, Qiryaqos F, et al. The SOS1 Inhibitor MRTX0902 Blocks KRAS activation and demonstrates antitumor activity in cancers dependent on KRAS nucleotide loading. Mol Cancer Ther. 2024. doi: 10.1158/1535-7163.MCT-23-0870
   PubMedGoogle Scholar
• Smith CR, Chen D, Christensen JG, et al. Discovery of five SOS2 fragment hits with binding modes determined by SOS2 X-Ray cocrystallography. J Med Chem. 2024;67(1):774–781. doi: 10.1021/acs.jmedchem.3c02140
   PubMed Web of Science ®Google Scholar
• Lake D, Corrêa SA, Müller J. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol Life Sci. 2016;73(23):4397–4413. doi: 10.1007/s00018-016-2297-8
   PubMed Web of Science ®Google Scholar
• Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420(6916):629–635. doi: 10.1038/nature01148
   PubMed Web of Science ®Google Scholar
• Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays. 2007;29(4):356–370. doi: 10.1002/bies.20558
   PubMed Web of Science ®Google Scholar
• Haga RB, Ridley AJ. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases. 2016;7(4):207–221. doi: 10.1080/21541248.2016.1232583
   PubMedGoogle Scholar
• Liu B, Xiong J, Liu G, et al. High expression of Rac1 is correlated with partial reversed cell polarity and poor prognosis in invasive ductal carcinoma of the breast. Tumor Biol. 2017;39(7):1010428317710908. doi: 10.1177/1010428317710908
   Google Scholar
• Stengel K, Zheng Y. Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cell Signal. 2011;23(9):1415–1423. doi: 10.1016/j.cellsig.2011.04.001
   PubMed Web of Science ®Google Scholar
• Fritz G, Brachetti C, Bahlmann F, et al. Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Br J Cancer. 2002;87(6):635–644. doi: 10.1038/sj.bjc.6600510
   PubMed Web of Science ®Google Scholar
• Ji J, Feng X, Shi M, et al. Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer. Int J Oncol. 2015;46(3):1343–1353. doi: 10.3892/ijo.2015.2836
   PubMed Web of Science ®Google Scholar
• Pan Y, Bi F, Liu N, et al. Expression of seven main rho family members in gastric carcinoma. Biochem Biophys Res Commun. 2004;315(3):686–691. doi: 10.1016/j.bbrc.2004.01.108
   PubMed Web of Science ®Google Scholar
• Kamai T, Yamanishi T, Shirataki H, et al. Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res. 2004;10(14):4799–4805. doi: 10.1158/1078-0432.CCR-0436-03
   PubMed Web of Science ®Google Scholar
• Liu SY, Yen CY, Yang SC, et al. Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. J Oral Maxillofac Surg. 2004;62(6):702–707. doi: 10.1016/j.joms.2004.02.002
   PubMed Web of Science ®Google Scholar
• Patel V, Rosenfeldt HM, Lyons R, et al. Persistent activation of Rac1 in squamous carcinomas of the head and neck: evidence for an EGFR/Vav2 signaling axis involved in cell invasion. Carcinogenesis. 2007;28(6):1145–1152. doi: 10.1093/carcin/bgm008
   PubMed Web of Science ®Google Scholar
• Takami Y, Higashi M, Kumagai S, et al. The activity of RhoA is correlated with lymph node metastasis in human colorectal cancer. Dig Dis Sci. 2008;53(2):467–473. doi: 10.1007/s10620-007-9887-0
   PubMed Web of Science ®Google Scholar
• Karlsson R, Pedersen ED, Wang Z, et al. Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 2009;1796(2):91–98. doi: 10.1016/j.bbcan.2009.03.003
   PubMed Web of Science ®Google Scholar
• Zhang S, Tang Q, Xu F, et al. RhoA regulates G1-S progression of gastric cancer cells by modulation of multiple INK4 family tumor suppressors. Mol Cancer Res. 2009;7(4):570–580. doi: 10.1158/1541-7786.MCR-08-0248
   PubMed Web of Science ®Google Scholar
• Zandvakili I, Davis AK, Hu G, et al. Loss of RhoA exacerbates, rather than dampens, oncogenic K-Ras induced lung adenoma formation in mice. PLoS One. 2015;10(6):e0127923. doi: 10.1371/journal.pone.0127923
   PubMed Web of Science ®Google Scholar
• Santos JC, Profitós-Pelejà N, Sánchez-Vinces S, et al. RHOA therapeutic targeting in hematological cancers. Cells. 2023;12(3):433. doi: 10.3390/cells12030433
   PubMed Web of Science ®Google Scholar
• Schaefer A, Der CJ. RHOA takes the RHOad less traveled to cancer. Trends Cancer. 2022;8(8):655–669. doi: 10.1016/j.trecan.2022.04.005
   PubMed Web of Science ®Google Scholar
• Maldonado MDM, Dharmawardhane S. Targeting rac and Cdc42 GTPases in cancer. Cancer Res. 2018;78(12):3101–3111. doi: 10.1158/0008-5472.CAN-18-0619
   PubMed Web of Science ®Google Scholar
• Liang J, Oyang L, Rao S, et al. Rac1, a potential target for tumor Therapy. Front Oncol. 2021;11:11. doi: 10.3389/fonc.2021.674426
   Web of Science ®Google Scholar
• Erasmus JC, Smolarczyk K, Brezovjakova H, et al. Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization. J Cell Bio. 2021;220(6). doi: 10.1083/jcb.202002114
   PubMed Web of Science ®Google Scholar
• Yuan Y, Zhang H, Li D, et al. PAK4 in cancer development: Emerging player and therapeutic opportunities. Cancer Lett. 2022;545:215813. doi: 10.1016/j.canlet.2022.215813
   PubMed Web of Science ®Google Scholar
• Mpilla GB, Uddin MH, Al-Hallak MN, et al. PAK4-NAMPT dual inhibition sensitizes pancreatic neuroendocrine tumors to Everolimus. Mol Cancer Ther. 2021;20(10):1836–1845. doi: 10.1158/1535-7163.MCT-20-1105
   PubMed Web of Science ®Google Scholar
• Maldonado MDM, Medina JI, Velazquez L, et al. Targeting Rac and Cdc42 GEFs in metastatic cancer. Front Cell Dev Biol. 2020;8:201. doi: 10.3389/fcell.2020.00201
   PubMed Web of Science ®Google Scholar
• Bannoura SF, Uddin MH, Nagasaka M, et al. Targeting KRAS in pancreatic cancer: new drugs on the horizon. Cancer Metastasis Rev. 2021;40(3):819–835. doi: 10.1007/s10555-021-09990-2
   PubMed Web of Science ®Google Scholar
• Joo E, Olson MF. Regulation and functions of the RhoA regulatory guanine nucleotide exchange factor GEF-H1. Small GTPases. 2021;12(5–6):358–371. doi: 10.1080/21541248.2020.1840889
   PubMedGoogle Scholar
• Chen X-Y, Cheng A-Y, Wang Z-Y, et al. Dbl family RhoGEFs in cancer: different roles and targeting strategies. Biochem Pharmacol. 2024;223:116141. doi: 10.1016/j.bcp.2024.116141
   PubMed Web of Science ®Google Scholar
• Boissier P, Huynh-Do U. The guanine nucleotide exchange factor Tiam1: a janus-faced molecule in cellular signaling. Cell Signal. 2014;26(3):483–491. doi: 10.1016/j.cellsig.2013.11.034
   PubMed Web of Science ®Google Scholar
• Permtermsin C, Lalchungnunga H, Nakjang S, et al. Identification of TIAM1 as a potential synthetic-lethal-like Gene in a defined subset of hepatocellular carcinoma. Int J Mol Sci. 2023;24(7):6387. doi: 10.3390/ijms24076387
   PubMed Web of Science ®Google Scholar
• Worthylake DK, Rossman KL, Sondek J. Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1. Nature. 2000;408(6813):682–688. doi: 10.1038/35047014
   PubMed Web of Science ®Google Scholar
• Gao Y, Dickerson JB, Guo F, et al. Rational design and characterization of a rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A. 2004;101(20):7618–7623. doi: 10.1073/pnas.0307512101
   PubMed Web of Science ®Google Scholar
• Dütting S, Heidenreich J, Cherpokova D, et al. Critical off-target effects of the widely used Rac1 inhibitors NSC23766 and EHT1864 in mouse platelets. J Thromb Haemost. 2015;13(5):827–838. doi: 10.1111/jth.12861
   PubMed Web of Science ®Google Scholar
• Cardama GA, Comin MJ, Hornos L, et al. Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anticancer Agents Med Chem. 2014;14(6):840–851. doi: 10.2174/18715206113136660334
   PubMed Web of Science ®Google Scholar
• Niebel B, Wosnitza CI, Famulok M. RNA-aptamers that modulate the RhoGEF activity of Tiam1. Bioorg Med Chem. 2013;21(20):6239–6246. doi: 10.1016/j.bmc.2013.05.021
   PubMed Web of Science ®Google Scholar
• Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov. 2010;9(7):537–550. doi: 10.1038/nrd3141
   PubMed Web of Science ®Google Scholar
• Katzav S. Vav1: a hematopoietic signal transduction molecule involved in human malignancies. Int J Biochem Cell Biol. 2009;41(6):1245–1248. doi: 10.1016/j.biocel.2008.11.006
   PubMed Web of Science ®Google Scholar
• Al-Hawary SIS, Alsalamy A, Gupta R, et al. VAV3 in human cancers: Mechanism and clinical implication. Pathol Res Pract. 2023;248:154681. doi: 10.1016/j.prp.2023.154681
   PubMed Web of Science ®Google Scholar
• Movilla N, Dosil M, Zheng Y, et al. How vav proteins discriminate the GTPases Rac1 and RhoA from Cdc42. Oncogene. 2001;20(56):8057–8065. doi: 10.1038/sj.onc.1205000
   PubMed Web of Science ®Google Scholar
• Zeng RJ, Zheng CW, Gu JE, et al. RAC1 inhibition reverses cisplatin resistance in esophageal squamous cell carcinoma and induces downregulation of glycolytic enzymes. Mol Oncol. 2019;13(9):2010–2030. doi: 10.1002/1878-0261.12548
   PubMed Web of Science ®Google Scholar
• Dharmawardhane S, Hernandez E, Vlaar C. Development of EHop-016: a small molecule inhibitor of Rac. Enzymes. 2013;33(Pt A(Pt A)):117–146.
   PubMedGoogle Scholar
• Montalvo-Ortiz BL, Castillo-Pichardo L, Hernández E, et al. Characterization of EHop-016, novel small molecule inhibitor of rac GTPase. J Biol Chem. 2012;287(16):13228–13238. doi: 10.1074/jbc.M111.334524
   PubMed Web of Science ®Google Scholar
• Castillo-Pichardo L, Humphries-Bickley T, De La Parra C, et al. The rac inhibitor EHop-016 inhibits mammary tumor growth and metastasis in a nude mouse Model. Transl Oncol. 2014;7(5):546–555. doi: 10.1016/j.tranon.2014.07.004
   PubMed Web of Science ®Google Scholar
• Humphries-Bickley T, Castillo-Pichardo L, Hernandez-O’Farrill E, et al. Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic cancer. Mol Cancer Ther. 2017;16(5):805–818. doi: 10.1158/1535-7163.MCT-16-0442
   PubMed Web of Science ®Google Scholar
• Borrero-García LD, Del Mar Maldonado M, Medina-Velázquez J, et al. Rac inhibition as a novel therapeutic strategy for EGFR/HER2 targeted therapy resistant breast cancer. BMC Cancer. 2021;21(1):652. doi: 10.1186/s12885-021-08366-7
   PubMed Web of Science ®Google Scholar
• Cruz-Collazo A, Ruiz-Calderon JF, Picon H, et al. Efficacy of rac and Cdc42 Inhibitor MBQ-167 in Triple-negative breast cancer. Mol Cancer Ther. 2021;20(12):2420–2432. doi: 10.1158/1535-7163.MCT-21-0348
   PubMed Web of Science ®Google Scholar
• Medina JI, Cruz-Collazo A, Maldonado M, et al. Characterization of novel derivatives of MBQ-167, an Inhibitor of the GTP-binding Proteins Rac/Cdc42. Cancer Res Commun. 2022;2(12):1711–1726. doi: 10.1158/2767-9764.CRC-22-0303
   PubMedGoogle Scholar
• Casalou C, Ferreira A, Barral DC. The Role of ARF family proteins and their regulators and effectors in cancer progression: a therapeutic perspective. Front Cell Dev Biol. 2020;8:217. doi: 10.3389/fcell.2020.00217
   PubMed Web of Science ®Google Scholar
• Chen P-W, Gasilina A, Yadav MP, et al. Control of cell signaling by arf GTPases and their regulators: focus on links to cancer and other GTPase families. Biochim Biophys Acta, Mol Cell Res. 2022;1869(2):119171. doi: 10.1016/j.bbamcr.2021.119171
   PubMed Web of Science ®Google Scholar
• Sztul E, Chen PW, Casanova JE, et al. ARF GTPases and their GEFs and GAPs: concepts and challenges. Mol Biol Cell. 2019;30(11):1249–1271. doi: 10.1091/mbc.E18-12-0820
   PubMed Web of Science ®Google Scholar
• Sandilands E, Freckmann EC, Cumming EM, et al. The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels. J Cell Bio. 2023;222(4). doi: 10.1083/jcb.202206115
   PubMed Web of Science ®Google Scholar
• Casanova JE. Regulation of arf activation: the Sec7 family of guanine nucleotide exchange factors. Traf. 2007;8(11):1476–1485. doi: 10.1111/j.1600-0854.2007.00634.x
   PubMed Web of Science ®Google Scholar
• Donaldson JG, Finazzi D, Klausner RD. Brefeldin a inhibits golgi membrane-catalysed exchange of guanine nucleotide onto ARF protein. Nature. 1992;360(6402):350–352. doi: 10.1038/360350a0
   PubMed Web of Science ®Google Scholar
• Zeghouf M, Guibert B, Zeeh JC, et al. Arf, Sec7 and Brefeldin A: a model towards the therapeutic inhibition of guanine nucleotide-exchange factors. Biochem Soc Trans. 2005;33(6):1265–1268. doi: 10.1042/BST0331265
   PubMedGoogle Scholar
• Davis JE, Xie X, Guo J, et al. ARF1 promotes prostate tumorigenesis via targeting oncogenic MAPK signaling. Oncotarget. 2016;7(26):39834–39845. doi: 10.18632/oncotarget.9405
   PubMedGoogle Scholar
• Boulay PL, Schlienger S, Lewis-Saravalli S, et al. ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein. Oncogene. 2011;30(36):3846–3861. doi: 10.1038/onc.2011.100
   PubMed Web of Science ®Google Scholar
• Gu G, Chen Y, Duan C, et al. Overexpression of ARF1 is associated with cell proliferation and migration through PI3K signal pathway in ovarian cancer. Oncol Rep. 2017;37(3):1511–1520. doi: 10.3892/or.2017.5388
   PubMed Web of Science ®Google Scholar
• Li R, Peng C, Zhang X, et al. Roles of Arf6 in cancer cell invasion, metastasis and proliferation. Life Sci. 2017;182:80–84. doi: 10.1016/j.lfs.2017.06.008
   PubMed Web of Science ®Google Scholar
• Hafner M, Schmitz A, Grüne I, et al. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature. 2006;444(7121):941–944. doi: 10.1038/nature05415
   PubMed Web of Science ®Google Scholar
• Wang H, Xiao Y, Zhou W, et al. Integrated analysis and validation reveal CYTH4 as a potential prognostic biomarker in acute myeloid leukemia. Oncol Lett. 2024;27(3):103. doi: 10.3892/ol.2024.14236
   PubMed Web of Science ®Google Scholar
• Ren WX, Guo H, Lin SY, et al. Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199. Acta Pharmacol Sin. 2024;45(1):180–192. doi: 10.1038/s41401-023-01142-2
   PubMed Web of Science ®Google Scholar
• Weizhong Z, Shuohui G, Hanjiao Q, et al. Inhibition of cytohesin-1 by siRNA leads to reduced IGFR signaling in prostate cancer. Braz J Med Biol Res. 2011;44(7):642–646. doi: 10.1590/S0100-879X2011007500072
   PubMed Web of Science ®Google Scholar
• Pan T, Sun J, Hu J, et al. Cytohesins/ARNO: the function in colorectal cancer cells. PLOS ONE. 2014;9(3):e90997. doi: 10.1371/journal.pone.0090997
   PubMed Web of Science ®Google Scholar
• Bill A, Schmitz A, König K, et al. Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells. PLoS One. 2012;7(7):e41179. doi: 10.1371/journal.pone.0041179
   PubMed Web of Science ®Google Scholar
• Dasso M. The Ran GTPase: theme and variations. Curr Biol. 2002;12(14):R502–508. doi: 10.1016/S0960-9822(02)00970-3
   PubMed Web of Science ®Google Scholar
• Hetzer M, Bilbao-Cortes D, Walther TC, et al. GTP hydrolysis by ran is required for nuclear envelope assembly. Mol Cell. 2000;5(6):1013–1024. doi: 10.1016/S1097-2765(00)80266-X
   PubMed Web of Science ®Google Scholar
• Carazo-Salas RE, Guarguaglini G, Gruss OJ, et al. Generation of GTP-bound ran by RCC1 is required for chromatin-induced mitotic spindle formation. Nature. 1999;400(6740):178–181. doi: 10.1038/22133
   PubMed Web of Science ®Google Scholar
• Fu X, Liang C, Li F, et al. The rules and functions of nucleocytoplasmic shuttling proteins. Int J Mol Sci. 2018;19(5):1445. doi: 10.3390/ijms19051445
   PubMed Web of Science ®Google Scholar
• Nachury MV, Weis K. The direction of transport through the nuclear pore can be inverted. Proc Nat Acad Sci. 1999;96(17):9622–9627. doi: 10.1073/pnas.96.17.9622
   PubMed Web of Science ®Google Scholar
• Izaurralde E, Kutay U, von Kobbe C, et al. The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus. Embo J. 1997;16(21):6535–6547. doi: 10.1093/emboj/16.21.6535
   PubMed Web of Science ®Google Scholar
• Bischoff FR, Ponstingl H. Catalysis of guanine nucleotide exchange on ran by the mitotic regulator RCC1. Nature. 1991;354(6348):80–82. doi: 10.1038/354080a0
   PubMed Web of Science ®Google Scholar
• Ohtsubo M, Okazaki H, Nishimoto T. The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J Cell Bio. 1989;109(4 Pt 1):1389–1397. doi: 10.1083/jcb.109.4.1389
   PubMed Web of Science ®Google Scholar
• Makde RD, England JR, Yennawar HP, et al. Structure of RCC1 chromatin factor bound to the nucleosome core particle. Nature. 2010;467(7315):562–566. doi: 10.1038/nature09321
   PubMed Web of Science ®Google Scholar
• Seki T, Hayashi N, Nishimoto T. RCC1 in the Ran pathway. J Biochem. 1996;120(2):207–214. doi: 10.1093/oxfordjournals.jbchem.a021400
   PubMed Web of Science ®Google Scholar
• El-Tanani M, Nsairat H, Mishra V, et al. Ran GTPase and its importance in cellular signaling and malignant phenotype. Int J Mol Sci. 2023;24(4):3065. doi: 10.3390/ijms24043065
   PubMed Web of Science ®Google Scholar
• Boudhraa Z, Carmona E, Provencher D, et al. Ran GTPase: a key player in tumor progression and metastasis. Front Cell Dev Biol. 2020;8:345. doi: 10.3389/fcell.2020.00345
   PubMed Web of Science ®Google Scholar
• Ren X, Jiang K, Zhang F. The multifaceted roles of RCC1 in Tumorigenesis. Front Mol Biosci. 2020;7:225. doi: 10.3389/fmolb.2020.00225
   PubMed Web of Science ®Google Scholar
• Bannoura SF, Aboukameel A, Khan HY, et al. Regulator of chromosome condensation (RCC1) a novel therapeutic target in pancreatic ductal adenocarcinoma drives tumor progression via the c-Myc-RCC1-Ran axis. bioRxiv. 2023 Dec 18;2023–12. doi: 10.1101/2023.12.18.572102
   Google Scholar
• Warnecke B, Nagasaka M, Hallak MNA, et al. Multi-omic characterization of RCC1 expression and its association with molecular alterations, immune phenotypes, and cancer outcomes. J Clin Oncol. 2023;41(16_suppl):3128–3128. doi: 10.1200/JCO.2023.41.16_suppl.3128
   Web of Science ®Google Scholar
• Huang T, Yang Y, Song X, et al. PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells. Mol Cell. 2021;81(6):1276–1291.e9. doi: 10.1016/j.molcel.2021.01.015
   PubMed Web of Science ®Google Scholar
• Wu Y, Xu Z, Chen X, et al. RCC1 functions as a tumor facilitator in clear cell renal cell carcinoma by dysregulating cell cycle, apoptosis, and EZH2 stability. Cancer Med. 2023;12(19):19889–19903. doi: 10.1002/cam4.6594
   PubMed Web of Science ®Google Scholar
• Zhuang M, Li F, Liang H, et al. Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2. Cell Death Dis. 2024;15(4):241. doi: 10.1038/s41419-024-06629-2
   PubMed Web of Science ®Google Scholar
• Gu S, Hou Y, Dovat K, et al. Synergistic effect of HDAC inhibitor chidamide with cladribine on cell cycle arrest and apoptosis by targeting HDAC2/c-Myc/RCC1 axis in acute myeloid leukemia. Exp Hematol Oncol. 2023;12(1):23. doi: 10.1186/s40164-023-00383-5
   PubMed Web of Science ®Google Scholar
• Haggag Y, Abu Ras B, El-Tanani Y, et al. Co-delivery of a RanGTP inhibitory peptide and doxorubicin using dual-loaded liposomal carriers to combat chemotherapeutic resistance in breast cancer cells. Expert Opin Drug Deliv. 2020;17(11):1655–1669. doi: 10.1080/17425247.2020.1813714
   PubMed Web of Science ®Google Scholar
• Haggag YA, Matchett KB, Falconer RA, et al. Novel ran-RCC1 inhibitory peptide-loaded nanoparticles have anti-cancer efficacy in vitro and in vivo. Cancers (Basel). 2019;11(2):222. doi: 10.3390/cancers11020222
   PubMed Web of Science ®Google Scholar
• Haggag YA, Matchett KB, Dakir EH, et al. Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cells. Int J Pharm. 2017;521(1–2):40–53. doi: 10.1016/j.ijpharm.2017.02.006
   PubMedGoogle Scholar