XPO1 (Exportin 1)

Data from the phase III BOSTON trial demonstrated that the selinexor-bortezomib-dexamethasone (SVd) combination is associated with a clinically meaningful benefit in terms of progression-free survival and overall survival in patients with relapsed MM, with a particularly relevant advantage in patients treated in the second-line setting who were not previously exposed to bortezomib. Overall, the SVd regimen may represent an effective and sustainable second-line therapeutic strategy, capable of combining antitumor activity with manageable tolerability, and addressing the clinical needs of a patient population increasingly representative of contemporary hematologic practice.

Conversely, doxorubicin reduced tumor size without affecting uptake, indicating preserved XPO1-associated signal. Together, these findings demonstrate that [18F]selinexor PET functions as a noninvasive imaging tool for evaluating the in vivo pharmacokinetics and pharmacodynamic behavior of selinexor, and capturing treatment-induced alterations in XPO1 engagement, although further structural optimization will be required prior to potential translation.

Cell lines representing DLBCL subtypes were treated with varying concentrations of the XPO1 inhibitor selinexor (XPO1i), cisplatin (CDDP), and oxaliplatin (OXA), alone or in combination. In OCI-Ly8 and OCI-Ly1 cells, OXA alone inhibited phosphorylation of AKT and mTOR while increasing phosphorylation of JNK, ATM, and p53, and expression of γH2AX; these effects were potentiated by the combination of XPO1i and OXA. XPO1 inhibition enhances platinum-induced cytotoxicity in GCB-DLBCL, supporting clinical evaluation of XPO1i-platinum combinations as salvage therapy.

Treatment of MM cells with the selective AURKA inhibitor LY3295668 induced dose-dependent cytotoxicity, caspase-3/7 activation, and cellular senescence. These findings underscore AURKA expression as a prognostic marker in plasma cell disorders and support the therapeutic potential of combining AURKA inhibition with selinexor for bortezomib-resistant MM and PCL. To explore biomarker-driven strategies for optimizing therapeutic outcomes, future studies are warranted.

A phase II is currently exploring this combination in leiomyosarcoma and malignant peripheral nerve sheath tumors. Trial registration: NCT04595994.

In addition, in vitro experiments indicated that circXPO1 knockdown significantly weakened the proliferation, invasion and migration of GC cells. It was also predicted that circXPO1 could serve as a sponge of miR-1248 to regulate the progression of GC.

Inhibition of XPO1 with selective inhibitors of nuclear export (SINE) compounds, including selinexor, has demonstrated the ability to restore nuclear localization and function of these proteins, thereby enhancing cellular sensitivity to DNA-damaging agents, kinase inhibitors, and immunotherapies. In preclinical NSCLC models, XPO1 inhibition has shown efficacy both as monotherapy and in combination strategies, with particular promise in KRAS- and EGFR-driven tumors. This review explores the role of XPO1 in NSCLC biology and therapy resistance, the rationale for targeting nuclear export, and the current landscape of XPO1-directed clinical development in lung cancer.

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.

Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1-cargo interaction...ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4.

Combination treatments significantly suppressed cell proliferation compared with single agents. These findings highlight the preclinical evidence of combining KPT-335 with conventional chemotherapies in canine lymphoma.

In this issue of Blood Cancer Discovery, Barajas and colleagues reveal that UBTF tandem duplications found in acute myeloid leukemia complete a nuclear export sequence that enables a novel UBTF-XPO1 interaction, particularly at chromatin loci critical for leukemogenesis, thus raising the question: Could XPO1 inhibitors find new use in the UBTF-TD acute myeloid leukemia subtype? See related article by Barajas et al., p. XX .

The main determinant of second-line therapy selection includes refractoriness, particularly to lenalidomide and anti-CD38 monoclonal antibodies, followed by cytogenetic risk, relapse aggressiveness, frailty, and patient preferences...Combinations based on belantamab mafadotin, an antibody drug conjugate targeting B cell maturation antigen (BCMA), are currently the leading non CAR-T options in this setting, while exportin-1 inhibitors, such as selinexor, and next-generation proteasome inhibitors offer additional options. Ongoing trials assessing T-cell redirecting bispecific antibodies targeting B cell maturation antigen or GPRC5D may further improve outcomes at first relapse as access and safety profiles evolve. In conclusion, early-relapse multiple myeloma care should be individualized in order to optimize patient outcomes and achieve long-term remissions with acceptable toxicity profile.