1 / 15

Selinexor Synergizes with Dexamethasone through Enhanced GR Activity

Selinexor Synergizes with Dexamethasone through Enhanced GR Activity. In Vitro Synergy with Selinexor / Dexamethasone combo. Previously demonstrated in vitro and in vivo synergy for selinexor/DEX combo in MM1.S cells. H929 MM cells. Selinexor IC 50 = 14 nM

barclay-sykes
Download Presentation

Selinexor Synergizes with Dexamethasone through Enhanced GR Activity

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Selinexor Synergizes with Dexamethasone through Enhanced GR Activity

  2. In Vitro Synergy with Selinexor/ Dexamethasone combo Previously demonstrated in vitro and in vivo synergy for selinexor/DEX combo in MM1.S cells H929 MM cells Selinexor IC50= 14 nM Dexamethasone IC50 = 2 nM Highly synergistic

  3. Multiple Myeloma and Dexamethasone Resistance • MM1R cells are resistant to dexamethasone due to loss of expression of the glucocorticoid receptor (GR) • Loss of GR may be only one reason for resistance and there are indications that overexpression of cytokines like IL-6 that affect the tumor micro environment may confer resistance in other cases • Since selinexor abrogates “microenvironment protection” of tumor by stroma cells, we hypothesize that synergism with GR is retained even in cases of IL-6 overexpression

  4. In Vivo Synergy with Selinexor-Dexamethasone Combo H929 MM xenografts

  5. Selinexor Synergizes with DEX to Induce the Transcriptional Activity of the the Glucocorticoid Receptor GR Transcriptional Activity • MM1.S cells were treated with either 1μM Selinexor, 100nM Dexamethasone or the combination for 4 h • Nuclear extracts from the cells were used by ELISA kit that quantifies the binding of the GR to its specific DNA consensus binding site in gene promoters

  6. Combination of Selinexor and Dexamethasone Attenuates NFκB Transcriptional Activity Better than the Single Agents MM1.S cells were pre-treated with either 1μM Selinexor, 100nM Dexamethasone or the both together for 2hrs, followed by 20ng/mL TNFastimulation for 4hrs in the presence of the drugs

  7. MOA: Selinexor Plus Dexamethasone Synergism • The Glucocorticoid receptor (GR) is an XPO1 cargo • While inactive in the cytoplasm GR is in a complex with HSP90, HSP70 and FKBP4 • Once cells are treated with dexamethasone, GR is phosphorylated, released from the complex and moves into the nucleus to activate gene expression • We found that selinexor increase nuclear retaining of GR (see below) • Locking GR in the nucleus increases GR transcription potency and inhibits NFκB Transcriptional Activity PhosphoSer 211 Glucocorticoid Receptor

  8. Induction of Apoptosis and Reduction in Tumor-cell-Number Post Selinexor-Dexamethasone Combination Treatment in Bone-marrow of MM Patients Pre-Treatment 3 wk Post Treatment Pre-Treatment 3 wkPost Treatment MM 040-081 PR 45mg/m2+20mg DEX MM 040-081 PR 45mg/m2+20mg DEX H&E CD138 MM 040-076 PR 45mg/m2+20mg DEX MM 040-076 PR 45mg/m2+20mg DEX Cleaved Casp. 3 FAS

  9. Selinexor is Synergistic with Proteasome Inhibitors in Selinexor Resistant Cell Lines

  10. Knocking Down IκB Greatly Suppresses Selinexor Potency ~70X decrease in KPT-330 cytotoxic potency after IκB knockdown by siRNA IκB siRNA 2 IκB siRNA 1 Control siRNA IκB Actin

  11. Basal NFκB Activity is Upregulated Selinexor Resistant Cells

  12. Selinexor/Proteasome Inhibitors Synergize in Selinexor Resistant Cells

  13. Increased Nuclear IκB with Sel/Bort Combo HT1080R fibrosarcoma (selinexor resistant) Increased nuclear IκB in cells treated with drug combination

  14. MOA: Selinexor Plus Proteasome Inhibitors Synergism • The IκB protein is an XPO1 cargo • While inactive in the cytoplasm, IκBis phosphorylated and degrades through the proteasome degradation machinery. In this case, NFκBis fully active and induces cell proliferation and inflammation • Proteasome inhibition by bortezomib protects phosphorylated IκBfrom degradation and inhibits NFκBactivity (published data) • The combination of bortezomib and Selinexor results in increased nuclear IκBwhich more efficiently inhibits (nuclear) NFκBtranscription activity and prevents XPO1 mediated IκB export

  15. Karyopharm Therapeutics Inc. NASDAQ: KPTI

More Related