Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Lapalombella, Rosa; Sun, Qingxiang; Williams, Katie; Tangeman, Larissa; Jha, Shruti; Zhong, Yun‐Shi; Goettl, Virginia M.; Mahoney, Emilia; Berglund, Caroline; Gupta, Sneha; Farmer, Alicia; Mani, Rajeswaran; Johnson, Amy J.; Lucas, David M.; Mo, Xiaokui; Daelemans, Dirk; Sandanayaka, Vincent; Shechter, Sharon; McCauley, Dilara; Shacham, Sharon; Kauffman, Michael; Chook, Yuh Min; Byrd, John C.

doi:10.1182/blood-2012-05-429506

Cited by 266 publications

(360 citation statements)

References 50 publications

(75 reference statements)

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“…Mechanistically, overexpression of XPO1 enhances export of nuclear tumor suppressor proteins such as p53, BRCA1, allophycocyanin, and NMP1, resulting in drug resistance. 33 Overexpression of XPO1 has also been associated with drug resistance and poor outcome in many solid tumors such as glioblastoma, cervical and ovarian cancer, [35][36][37] and various hematologic malignancies, including myeloma, 38 chronic lymphocytic leukemia, 26 T-cell acute lymphoblastic leukemia, acute myeloid leukemia, [39][40][41] and BCR-ABL1-driven blastic transformation. 19,42 In the shRNA library screen, shRAN-infected cells were depleted by fourfold in K562 R compared with K562 S cells (supplemental Table 4) following 9 days in culture.…”

Section: Discussionmentioning

confidence: 99%

“…19,26 Similar to shRNA-mediated RAN knockdown ( Figure 4C), KPT-330 (72 hours, 50 nM) induced apoptosis of TKI-sensitive and TKI-resistant K562 and AR230 cells in vitro (supplemental BLOOD Figure 3). However, when CML cell lines were treated with graded concentrations of KPT-330 for 72 hours, the IC 50 was 2-and 1.4-fold lower in K562 R and AR230 R cells, respectively, compared with parental counterparts (supplemental Table 5), suggesting that TKIresistant cells are indeed more sensitive to XPO1 inhibition than TKI-sensitive cells.…”

Section: Inhibition Of the Ran-xpo1-set Pathway Impairs Survival Of Cmentioning

confidence: 99%

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shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Khorashad

Eiring

Mason

et al. 2015

Blood

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The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562 R , a CML cell line with BCR-ABL1 kinaseindependent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562 R cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34 1 cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34 1 cells from normal cord blood or from a patient harboring the BCR-ABL1 T315I mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML. (Blood. 2015;125(11):1772-1781

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Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of the Ran-xpo1-set Pathway Impairs Survival Of Cmentioning

confidence: 99%

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Khorashad

Eiring

Mason

et al. 2015

Blood

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“…The severe toxicity profile of LMB has prevented its further clinical development (44). Toxicities have been attributed to off-target effects due to its binding to several cysteine proteases, in addition to the irreversible inhibition of XPO1 (45).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

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“…Alkylation of Cys528 prevents XPO1 from binding to the leucine-rich nuclear export sequence of the cargo protein substrate, hence inhibiting the formation of the XPO1-cargo-RanGTP export complex and effectively blocking nuclear export ( 3 , 29 ). There are now data suggesting that the severe toxicities observed following treatment with Leptomycin-B involve additional off-target effects caused by binding to cysteine proteases as well as the irreversible blockade of all XPO1 functions per se ( 68 ). Therefore, a selective and reversible inhibitor might possess potent anticancer activity with an improved tolerability profi le.…”

Section: Naturally Derived Xpo1 Inhibitorsmentioning

confidence: 99%

“…The major adverse event across all tested species to date (mice, rats, dogs, and monkeys) is reversible weight reduction accompanied by reduced food intake without signifi cant vomiting or diarrhea ( 79 ). The improved toxicity profi le of these newer XPO1 inhibitors relative to previous XPO1 inhibitors, such as Leptomycin-B, is thought to be related to their exquisite specifi city for XPO1 with no detectable binding to other proteins, including the cysteine proteases, believed to be the cause of poor tolerance to Leptomycin-B ( 68 ).…”

Section: Reviewmentioning

confidence: 99%

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

et al. 2014

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In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed. Signifi cance:The nuclear transport mechanism is dysregulated in many malignancies and is associated with dysfunction of many regulatory proteins. Targeting this mechanism as an anticancer strategy has been compelling, and novel agents that selectively inhibit the nuclear export pathway have demonstrated preliminary evidence of clinical effi cacy with an acceptable safety profi le. Cancer Discov; 4(5); 527-37.

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Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

Cited by 266 publications

References 50 publications

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

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