XPO1 nuclear export

Current understanding

XPO1 (exportin-1) mediates nuclear export of tumor suppressors and oncogenic transcripts; pharmacologic XPO1 inhibition (e.g., selinexor) is being tested as a mechanistically orthogonal partner to JAK-STAT blockade in MPN. Phase 3 SENTRY data (selinexor + ruxolitinib in MF) provide the first late-stage clinical evidence that XPO1 inhibition contributes to spleen volume reduction and produces driver-allele (JAK2/MPL/CALR) burden reductions on top of ruxolitinib, though symptom-burden benefit was not demonstrated.

Evidence log

• 2026-06-02 — Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor-Naïve Myelofibrosis: Phase III SENTRY Trial.: Phase III SENTRY (JAKi-naïve MF) confirms selinexor + ruxolitinib significantly improves SVR35 at week 24 versus ruxolitinib alone with an early OS signal, but fails to improve AbsTSS, validating XPO1 inhibition as a mechanistically orthogonal spleen-directed partner while leaving the symptom-benefit question open. (novelty: 3)
• 2026-07-14 — Targeting nuclear export and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling in myelofibrosis: A novel combinatorial strategy that impacts intrinsic and microenvironment-related pathways.: Preclinical multi-omic study shows selinexor + ruxolitinib restores nuclear tumor suppressors and outperforms JAK2 inhibition alone in suppressing MF progenitor fitness, including in ruxolitinib-resistant models, with dual cell-intrinsic and microenvironment effects. (novelty: 3)
• 2026-07-02 — A Study to Evaluate Single Agent Selinexor Versus Physician’s Choice in Participants With Previously Treated Myelofibrosis: Phase 2 randomized open-label trial compares selinexor monotherapy against physician’s choice in MF patients with ≥6 months of prior JAK1/2 inhibitor exposure, providing the first head-to-head randomized test of single-agent XPO1 inhibition in the post-JAKi setting. (novelty: 3)
• 2026-06-08 — Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors: Phase II single-arm trial evaluates selinexor monotherapy in primary/secondary MF refractory or intolerant to ruxolitinib and/or other JAK1/2 inhibitors, testing whether XPO1 inhibition alone can salvage patients failing catalytic JAK-STAT blockade rather than requiring a JAKi backbone. (novelty: 3)
• 2026-06-04 — Selinexor Monotherapy for Cytoreduction in BCR::ABL1-Negative Myeloproliferative Neoplasms: Phase II single-arm trial evaluates selinexor monotherapy (no JAK inhibitor backbone) as cytoreductive therapy across BCR::ABL1-negative MPNs (PV, ET, PMF) over 6 months, testing whether XPO1 inhibition alone is sufficient to lower hematologic burden rather than serving only as a combination partner. (novelty: 4)
• May 21, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Review highlights SENTRY meeting its first co-primary endpoint (spleen volume reduction with selinexor + ruxolitinib in first-line MF) as validating XPO1 inhibition as a frontline combination partner alongside other emerging MPN combination regimens. (novelty: 3)
• May 12, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Review reiterates selinexor (XPO1 inhibitor) as one of the key emerging mechanistically orthogonal agents in the active MPN trial landscape, alongside pelabresib and imetelstat. (novelty: 3)
• 2026-03-18 — Selinexor and Pacritinib in JAK Inhibitor-naïve MF Patients With Cytopenias: Phase II trial of selinexor + pacritinib in JAKi-naïve cytopenic MF tests whether XPO1 inhibition can be safely combined with a platelet-sparing JAK2/IRAK1 inhibitor, extending XPO1+JAK combinations beyond the SENTRY ruxolitinib backbone into anemic/thrombocytopenic patients. (novelty: 4)
• 2026-03-24 — Karyopharm Phase 3 SENTRY Trial in Myelofibrosis Met First Co-Primary Endpoint: cross-connection with jak-stat-signaling: SENTRY Phase 3 demonstrates that XPO1 inhibition layered on JAK-STAT blockade produces additive spleen and allele-burden responses, establishing nuclear export as a clinically validated orthogonal axis to JAK2 signaling in MF. (novelty: 4)

Open questions

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