eltanexor (KPT-8602) / Ono Pharmaceutical, Karyopharm, Antengene - LARVOL DELTA

Selinexor and Venetoclax Combination in Patients With Relapsed or Refractory Acute Myeloid Leukemia. (PubMed, Am J Hematol) - P1 | "Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640)."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Thrombocytopenia • MCL1

A clinically translatable next-generation EVA strategy for glioblastoma: combining eltanexor and BH3-mimetics drives synergistic apoptosis. (EANO 2026) - "Background:Glioblastoma (GB) is characterized by marked aggressiveness, poor clinical outcome, and rapid development of resistance to currently available treatments. Replacing the original Venetoclax/A1210477 backbone with Navitoclax and a clinically advanced MCL-1 inhibitor resulted in substantially enhanced anti-glioblastoma activity and robust synergistic effects, with MIK665 showing superior performance compared with S63845 across experiments. These data support further development of Navitoclax and MIK665 as core components of a next-generation EVA strategy with strong translational potential."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • CASP3

Preclinical characterization of a reversible XPO1 inhibitor for cancer therapy. (PubMed, Nat Commun) - "In contrast to clinical-stage XPO1 inhibitors selinexor and eltanexor, FR-027 acts reversibly and does not promote XPO1 protein degradation. Notably, FR-027 does not induce significant thrombocytopenia, lymphopenia, or neutropenia in heavily treated mice. These findings underscore the distinct molecular and pharmacological properties of FR-027 and support its further evaluation for clinical development in diseases with significant unmet medical needs."

Journal • Preclinical • Developmental Disorders • Hematological Disorders • Neutropenia • Oncology • Targeted Protein Degradation • Thrombocytopenia • XPO1

XPO1 inhibition enhances the efficacy and durability of RAS-targeted therapy in preclinical models of KRASG12D mutant pancreatic ductal adenocarcinoma. (PubMed, Cancer Lett) - "Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC."

IO biomarker • Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • XPO1

Selinexor as a multi-pathway regulator of the XPO1-inflammation Axis: Mechanisms, evidence in inflammatory diseases, and translational challenges. (PubMed, Int Immunopharmacol) - "This review emphasizes a stepwise translational logic from protein turnover and receptor regulation to next-generation XPO1 inhibitors. At present, selinexor is more suitable as a mechanistic tool for exploring the XPO1-inflammation axis, whereas inflammatory-disease translation will require eltanexor or related agents with more favorable tissue distribution and tolerability, together with precisely stratified clinical studies."

Journal • Review • Infectious Disease • Inflammation • Novel Coronavirus Disease • Oncology • NLRP3

ONCOGENIC MECHANISMS AND THERAPEUTIC TARGETING OF THE HIGH-RISK CDX2/UBTF B-ALL (EHA 2026) - "Ongoing analyses aim to clarify the transcriptional and epigenetic consequences of XPO1 inhibition and to further validate this therapeutic approach for clinical translation. CDX2/UBTF B-ALL are sensitive to XPO1 inhibitors (A) Experimental setup of the ex-vivo drug screening (B) Dose response curves to the XPO1 inhibitor Eltanexor in 4 independent CDX2/UBTF PDX with the projection (in grey) of the 10th and 90th quantile of the cohort (C) Experimental setup of in-vivo treatment in NSG mice with 10mg/kg Eltanexor (D) Bio-luminescence images (E) Bio-luminescence total flux quantification (F) Bone marrow aspirates after 4 weeks of treatment."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • CDX2 • MEIS1

Synergistic Antitumor Activity of HAT Inhibitor A485 and XPO1 Inhibitor KPT8602 in Multiple Myeloma. (PubMed, Cancer Med) - "Our findings position p300 as a central architect of pathogenic chromatin activation in MM. The combination of HAT inhibition (A485) and nuclear export inhibition (KPT8602) represents a novel, mechanistically rationalized therapeutic strategy to overcome epigenetic plasticity in MM."

IO biomarker • Journal • CNS Disorders • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Psychiatry • IRF4

Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer. (PubMed, bioRxiv) - "Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • EIF4A1 • XPO1

Targeting the nuclear export receptor exportin-1 in acute myeloid leukaemia: From biology to clinical translation. (PubMed, Clin Transl Med) - "XPO1 hyperactivation rewires nucleocytoplasmic transport and sustains leukaemogenic programs in genetically defined acute myeloid leukaemia (AML) subsets. Selective XPO1 inhibitors (selinexor, eltanexor) show preferential activity in NPM1-mutated, DEK::NUP214-positive and SF3B1-mutated myeloid neoplasms. Combination strategies with hypomethylating agents, BCL-2 inhibitors and other targeted therapies enhance depth and durability of responses but are limited by toxicity. Future clinical trials should focus on molecularly selected populations, biomarker-guided dosing and translational endpoints such as measurable residual disease (MRD) and clonal dynamics."

IO biomarker • Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NPM1 • NUP214 • SF3B1 • XPO1

The in vivo impact of UBTF tandem duplications on hematopoiesis and leukemia development (AACR 2026) - "Collectively, our work demonstrates that UBTF-TD is sufficient to drive leukemia development in vivo and that this model recapitulates key phenotypes observed in UBTF-TD AMLs. This mouse model provides a platform for evaluating leukemia initiation, progression, and therapeutic vulnerabilities, including XPO1 inhibition (eltanexor) and Menin inhibition (revumenib), both of which have demonstrated efficacy in cbCD34 and patient-derived xenograft (PDX) UBTF-TD models."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • ITGAM • KMT2A • MEIS1 • NR3C1

Small-molecule screening of HiBiT-tagged PAX3::FOXO1 rhabdomyosarcoma cell lines identifies eltanexor as a potent therapeutic agent against fusion-positive rhabdomyosarcoma (AACR 2026) - "The screen identified 183 hits, including Eltanexor, an XPO1 inhibitor. XPO1 exports over 200 proteins from the nucleus by recognizing their nuclear export sequences (NESs). Since the fusion gene retains the NES of FOXO1, a known XPO1 target, we tested whether PAX3::FOXO1 is a substrate."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • BRD4 • MYCN • PAX3

Efficacy of an XPO1 inhibitor in combination with irinotecan in a preclinical colorectal cancer model. (PubMed, Front Oncol) - "Using preclinical CRC PDX and cell line models, we evaluated the therapeutic potential of selinexor or eltanexor (XPO1 inhibitors), as a single agent and in combination with chemotherapeutic agents. In our mechanistic studies, elevation of p53 nuclear/cytoplasmic ratio and the activation of H2A.X suggests that the addition of eltanexor to irinotecan may facilitate its cellular effects by preventing the repair of DNA damage and inducing apoptosis. This preclinical CRC study demonstrates that combining eltanexor with irinotecan enhances cytotoxicity and anti-tumor effects in a subset of preclinical CRC PDX and cell line models, and that sequential treatment with irinotecan first may be most effective in inducing these treatment effects in the combination responsive CRC models."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

Combinations of Cdc-like kinase (CLK) inhibitors with targeted oncology agents or standard chemotherapy in patient-derived multi-cell type tumor spheroids (AACR 2024) - "Among the standard chemotherapeutic drugs, doxorubicin and SN-38 demonstrated additive and greater-than-additive cytotoxicity in various spheroid types when combined with either CLK inhibitor...These agents included the XPO1 inhibitor, eltanexor, the MCL-1 inhibitor, tapotoclax, the α-isoform-specific PI3K inhibitor, inavolisib, and the pan-PI3K inhibitor, copanlisib. Notably, combinations of the CLK inhibitors with the KRAS G12D variant-specific inhibitor, MRTX-1133, showed selective activity against all tumor cell lines harboring this genetic variant. Interestingly, a strong antagonistic interaction between paclitaxel and CC-671 was observed in all thirty spheroid types, while no such interaction was observed with cirtuvivint. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I."

Clinical • Melanoma • Oncology • Solid Tumor • KRAS

Inhibition of BCL2 and XPO1 demonstrates synergistic effects in triple-negative breast cancer cell lines (AACR 2024) - "The aim of this study was to evaluate eltanexor (Elta), an XPO1 inhibitor, in combination with venetoclax (Ven), a Bcl-2 inhibitor to promote apoptosis in TNBC models. CellTiter-Glo Cell Viability Assay was utilized to determine cell viability in 6 TNBC cell lines after 72-hour exposure to no drug, Elta, Ven or the combination...Synergy was observed in CAL-120, BT-20, and MDA-MB-468 cell lines, with synergy score values ranging from -13.22 - 25.07... The combination of Elta and Ven resulted in increased apoptosis and antiproliferative activity in TNBC cell lines. Combined, the two drugs synergistically functioned to increase DNA damage and promote apoptotic cell death. This work supports the continued evaluation of Elta and Ven in TNBC."

IO biomarker • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • BCL2 • HER-2 • MCL1 • PGR

Exportin 1 as a novel therapeutic target in gastroenteropancreatic neuroendocrine tumors (AACR 2025) - "Selective inhibitors of nuclear export (SINE) selinexor and eltanexor suppressed the growth of BON-1 and QGP-1 cells at pharmacologically relevant concentrations...Selinexor synergized with everolimus and sunitinib leading to superior pNET cell deaths (combination index<1)... This is the first study to reveal the therapeutic potential of novel XPO1-targeted agents for the treatment of a GEP-NET in vitro and in vivo. XPO1 could be a novel therapeutic target that warrants further clinical investigations in GEP-NETs."

IO biomarker • Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • CHGA • DAXX • FANCD2 • RICTOR • SMAD3 • XPO1

Next generation nuclear export blocker KPT8602 synergizes with KRASG12D inhibitor MRTX1133 resulting in improved antitumor effects against pancreatic ductal adenocarcinoma (AACR 2024) - "Nevertheless, given the clinical experience with sotorasib (a KRASG12C inhibitor) in lung cancer, it's anticipated that resistance to the KRASG12D inhibitor will eventually emerge in most PDAC patients. This is the first study demonstrating that nuclear export blocker KPT8602 can synergize with KRASG12D inhibitor MRTX1133 and has the potential to target MRTX1133-resistant PDAC cells. This study provides a rationale for combining MRTX1133 with KPT8602 for the treatment of PDAC patients with KRASG12D mutant tumors."

IO biomarker • Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • XPO1

Targeting XPO1 to enhance the durability of response of MRTX1133 in pancreatic ductal adenocarcinoma (AACR 2025) - "This is the first study showing that KPT8602 treatment can overcome resistance to MRTX1133 and synergistically augment the antitumor effects of MRTX1133 in PDAC preclinical models. This combination regimen can potentially prevent or delay drug resistance by making it feasible to achieve a more durable response at a lower dose of KRASG12D inhibitor."

IO biomarker • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CCND1 • DUSP6 • EIF4EBP1 • KRAS • mTOR

XPO1 inhibition serves as an effective chemoprevention strategy in colorectal cancer mouse models (AACR 2025) - "Moreover, to further evaluate Eltanexor's potential role in chemoprevention, Eltanexor was administered to Apcmin/+ mice with celecoxib, a COX-2 inhibitor shown previously to effectively limit Apcmin/+ mice tumorigenesis. Our findings show XPO1 inhibition using the small molecule Eltanexor results in inhibition of the Wnt/ β-catenin signaling pathway, a crucial pathway in CRC tumorigenesis. Furthermore, we show that Eltanexor treatment is an effective chemoprevention strategy in Apcmin/+ mice, a FAP mouse model. These findings highlight a promising chemopreventive strategy for high-risk CRC individuals."

IO biomarker • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • FOXO3 • PTGS2 • XPO1

Effect of XPO1 inhibition on colorectal cancer tumorigenesis (AACR 2024) - "Collectively, our findings underscore XPO1 as a potent target for inhibiting CRC tumorigenesis. Future studies will aim to further assess how Eltanexor is impacting COX-2's promoter, while additionally testing Eltanexor's tumorigenesis-inhibiting potential in a colitis-induced CRC mouse model."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PTGS2 • XPO1

Νοvel Therapies in High-Risk Myelodysplastic Syndromes. (PubMed, Eur J Haematol) - "Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies."

Journal • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HAVCR2 • IDH1 • IDH2

KPT-8602 combined with IFN-γ released ZBP1-PANoptosome to inhibit the progression of primary central nervous system lymphoma. (PubMed, Exp Cell Res) - "The combination of KPT-8602 and IFN-γ can activate the pan-apoptotic pathway by upregulating ZBP1, thereby effectively inhibiting the growth of PCNSL. This study presented a promising new combination treatment strategy for PCNSL."

Journal • B Cell Lymphoma • Burkitt Lymphoma • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • CXCL13 • IFNG • IGF2BP1 • IL18 • IL1B • IL6 • ZBP1

Co-targeting KRAS and Exportin1 as an effective therapeutic strategy for KRASG12D mutant pancreatic ductal adenocarcinoma. (PubMed, bioRxiv) - "Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CCND1 • DUSP6 • EIF4EBP1 • KRAS • XPO1

UBTF tandem duplications generate a nuclear export signal motif that drives an XPO1 dependency in leukemia (ASH 2025) - "Disrupting this axis, genetically (NES-M) orpharmacologically (eltanexor), impairs chromatin targeting, induces differentiation, and suppressesleukemogenesis. These findings nominate XPO1 as a dependency in UBTF-TD AML and support clinicalevaluation of XPO1 inhibitors in this subtype."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD33 • CD34 • ITGAM • KIT • KMT2A • MEIS1 • NPM1 • PTPRC • XPO1

Targeting β-catenin nuclear export and protein degradation in high-risk acute lymphoblastic leukemia (ASH 2025) - "The combination of Selinexorwith GSK3B inhibition (LY2090314) or PSMB8/PSMB9 inhibition (Zetomipzomib/ONX0914) resulted insynergistic nuclear β-catenin accumulation in reporter cells...The identification of β-catenin as an XPO1 cargo protein and thenucleus as a shelter from protein degradation provide a mechanistic rationale for combining XPO1inhibition (selinexor, eltanexor) with GSK3B or immunoproteasome inhibition, which will support thedesign of forthcoming in vivo studies, including xenograft-based preclinical efficacy models in patient-derived B- and T-ALL xenografts. These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL... These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL. Our finding supports a promising combinatorial strategy for thetreatment of r/r ALL by co-targeting nuclear export and β-catenin protein..."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • PSMB8 • PSMB9 • XPO1

Therapeutic horizons in targeting XPO1 with small inhibitor molecules: Recent achievements, synthetic strategies, opportunities, challenges, and future perspectives. (PubMed, Bioorg Chem) - "The FDA approval of Selinexor marked a major milestone followed by second-generation compounds such as Eltanexor and Verdinexor. This review highlights the therapeutic applications, biological roles, the mechanisms of inhibition, recent preclinical and clinical achievements, and emerging opportunities in anticancer and antiviral therapeutics mediated by XPO1 inhibition. Specifically, this review emphasizes the detailed adopted chemical strategies for the development of XPO1 small molecule inhibitors and their emerging inhibition mechanisms, aiming to support future XPO1 inhibitor design."

Journal • Review • Oncology