The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia

Verbeke, Delphine; Demeyer, Sofie; Prieto, Cristina; Bock, Charles E. de; Bie, Jolien De; Gielen, Olga; Jacobs, Kris; Mentens, Nele; Verhoeven, Bronte Manouk; Uyttebroeck, Anne; Boeckx, Nancy; Keersmaecker, Kim De; Maertens, Johan; Segers, Heidi; Cools, Jan

doi:10.1158/1078-0432.ccr-20-1315

Cited by 21 publications

(17 citation statements)

References 57 publications

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“…CRM1 specific inhibitors are being used in clinical trials as a target for number of cancer therapies including non-Hodgkin lymphomas ( [63,64] and reviewed in [65,66]). Of interest, a CRM1 inhibitor showed anticancer activity in a JAK3 mutant mouse model for T-ALL [67,68] suggesting the highly interesting possibility that shifting the dynamics of nuclear import/export and the balance between nuclear and cytoplasmic JAK3 might also be a novel potential target for therapy in CTCL. Accordingly, CRM1 inhibitors could be of interest to test as novel remedies for inhibition of malignant T cells in CTCL as it regulates the activity of JAK3/STAT3/SOCS3, a key signaling pathway in malignant transformation in CTCL [17].…”

Section: Discussionmentioning

confidence: 99%

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Vadivel

Gluud

Torres-Rusillo

et al. 2021

Cancers

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Perturbation in JAK-STAT signaling has been reported in the pathogenesis of cutaneous T cell lymphoma (CTCL). JAK3 is predominantly associated with the intra-cytoplasmic part of IL-2Rγc located in the plasma membrane of hematopoietic cells. Here we demonstrate that JAK3 is also ectopically expressed in the nucleus of malignant T cells. We detected nuclear JAK3 in various CTCL cell lines and primary malignant T cells from patients with Sézary syndrome, a leukemic variant of CTCL. Nuclear localization of JAK3 was independent of its kinase activity whereas STAT3 had a modest effect on nuclear JAK3 expression. Moreover, JAK3 nuclear localization was only weakly affected by blockage of nuclear export. An inhibitor of the nuclear export protein CRM1, Leptomycin B, induced an increased expression of SOCS3 in the nucleus, but only a weak increase in nuclear JAK3. Importantly, immunoprecipitation experiments indicated that JAK3 interacts with the nuclear protein POLR2A, the catalytic subunit of RNA Polymerase II. Kinase assays showed tyrosine phosphorylation of recombinant human Histone H3 by JAK3 in vitro—an effect which was blocked by the JAK inhibitor (Tofacitinib citrate). In conclusion, we provide the first evidence of nuclear localization of JAK3 in malignant T cells. Our findings suggest that JAK3 may have a cytokine-receptor independent function in the nucleus of malignant T cells, and thus a novel non-canonical role in CTCL.

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Section: Discussionmentioning

confidence: 99%

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Vadivel

Gluud

Torres-Rusillo

et al. 2021

Cancers

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“…Moreover, these drugs also potently inhibited cluster A cancers, revealing general YAP off selectivity (Figures 4F and S4D). Notably, aurora kinase inhibitors are synthetic lethal with RB1 loss (Gong et al, 2019;Oser et al, 2019), which is enriched in YAP off solid cancers (Figure 3E), and XPO1 and BCL or HDAC inhibitors are potent against leukemia and SCN tumors, respectively (Balanis et al, 2019;Verbeke et al, 2020). We validated several YAP off -selective drugs, and expressing YAP and/or constitutively active YAP S5A reduced sensitivity in several YAP off cancer types (Figures 4G and 4H).…”

Section: Yap/taz and Integrin/adhesion Genes Stratify Binary Pan-cancer Classesmentioning

confidence: 99%

Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

et al. 2021

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“…Similarly, imatinib could be used for rare T-ALL cases with ABL1 fusions, but case reports have shown variable efficacy in this setting [18] . Recently, selective inhibition of nuclear export by the second-generation exportin-1 (XPO1) inhibitor KPT-8602 (eltanexor) was shown to induce apoptosis in various cancer types, including ALL [19 , 20] , without deleterious effects to normal hematopoiesis [21] . Interestingly, the cancer-specific properties of this small molecule do not require specific mutations and previous studies in ALL have shown a general sensitivity of ALL cells for KPT-8602, independent of any genomic markers [19 – 21] .…”

Section: Introductionmentioning

confidence: 99%

PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia

et al. 2021

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Background T cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype that comprises 10–15% of childhood and 20–25% of adult ALL cases. Over 70% of T-ALL patients harbor activating mutations in the NOTCH1 signaling pathway and are predicted to be sensitive to gamma-secretase inhibitors. We have recently demonstrated that selective inhibition of PSEN1-containing gamma-secretase complexes can overcome the dose-limiting toxicity associated with broad gamma-secretase inhibitors. In this study, we developed combination treatment strategies with the PSEN1-selective gamma-secretase inhibitor MRK-560 and other targeted agents (kinase inhibitors ruxolitinib and imatinib; XPO-1 inhibitor KPT-8602/eltanexor) for the treatment of T-ALL. Methods We treated T-ALL cell lines in vitro and T-ALL patient-derived xenograft (PDX) models in vivo with MRK-560 alone or in combination with other targeted inhibitors (ruxolitinib, imatinib or KPT-8602/eltanexor). We determined effects on proliferation of the cell lines and leukemia development and survival in the PDX models. Results All NOTCH1-signaling-dependent T-ALL cell lines were sensitive to MRK-560 and its combination with ruxolitinib or imatinib in JAK1- or ABL1-dependent cell lines synergistically inhibited leukemia proliferation. We also observed strong synergy between MRK-560 and KPT-8602 (eltanexor) in all NOTCH1-dependent T-ALL cell lines. Such synergy was also observed in vivo in a variety of T-ALL PDX models with NOTCH1 or FBXW7 mutations. Combination treatment significantly reduced leukemic infiltration in vivo and resulted in a survival benefit when compared to single treatment groups. We did not observe weight loss or goblet cell hyperplasia in single drug or combination treated mice when compared to control. Conclusions These data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.

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The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia

Cited by 21 publications

References 57 publications

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity

PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia

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