XPO1, also known as chromosome region maintenance 1 (CRM1), recognizes and binds to proteins containing nuclear export signals (NES) and, under the direction of energy and directionality provided by Ran GTPase proteins, promotes the export of these proteins from the nucleus to the cytoplasm through the nuclear pore complex (NPC) (Nachmias and Schimmer, 2020). XPO1 primarily exports tumor suppressor proteins (TSPs), including p53, p21, and FOXO3A. The mislocalization of these proteins can disrupt their antitumor functions (Nachmias and Schimmer, 2020). The abnormal nuclear export of the above proteins leads to the inactivation of protein function, increased drug resistance, and abnormal proliferation and differentiation of tumor cells (Hutten and Kehlenbach, 2007; Gravina et al., 2014). Kojima et al. (Kojima et al., 2013) detected the expression level of XPO1 protein in 511 de novo AML patients and variable analysis showed that high expression of XPO1 is an independent predictor of overall survival (OS), which is related to high-risk cytogenetics and shorter survival.

However, selinexor (Selinexor), a selective inhibitor of nuclear export protein XPO1 and a highly selective, reversible binding small molecule oral nuclear export protein inhibitor compound (SINE), can covalently bind to the cysteine 528 site in the leucine-rich nuclear export signal (NES) binding region of XPO1, slowly and reversibly inhibiting the nuclear export function of XPO1(Figure 2), restoring the activity of TSP, and playing a role in promoting apoptosis and anti-tumor activity, while allowing a certain degree of nuclear export to ensure the survival and function of normal cells (Grayton et al., 2017; Etchin et al., 2016). Selinexor exhibits remarkable cytotoxicity against AML cells, while exerting no apparent effects on normal hematopoietic stem cells (Etchin et al., 2013) and progenitor cells (Etchin et al., 2015). Experimental studies have shown that in AML, XPO1 inhibitors can act on the following key TSP.

In addition, studies have shown that XPO1 inhibitors can downregulate the expression levels of DNA repair genes (Rad51 and Chk1) dependent on c-myc gene, inhibit homologous recombination repair of tumor cells, and promote the nuclear localization of Topo IIa, restoring the drug sensitivity of Topo IIa inhibitors (Ranganathan et al., 2016). Ranganathan et al. (Ranganathan et al., 2015) also found that sequential treatment of AML cells with decitabine followed by XPO1 inhibitors can upregulate the expression of CDKN1A and FOXO3A, enhance anti-leukemia activity, and significantly extend the survival of AML mice compared to monotherapy with selinexor. The above preclinical studies provide theoretical support for the clinical research exploration of XPO1-targeted therapy in the AML field. As the only approved selective XPO1 inhibitor, selinexor has undergone extensive early clinical research in the AML field.

Selinexor is rapidly absorbed after oral administration, with an average time to reach maximum concentration of 2–4 h (Gounder et al., 2016; Razak et al., 2016; Alexander et al., 2016). Studies have shown that the peak induction of XPO1 mRNA occurs 4–8 h after the initial administration of selinexor, and its elevated levels persist for 24–48 h (Garzon et al., 2017). This means that selinexor can slowly and continuously inhibit XPO1 for up to 48 h after achieving target occupancy. The possible reason is the effect achieved by the overlapping half-life of multiple selinexor doses. Selinexor is mainly metabolized by the liver and eliminated by the biliary system, with an elimination half-life of 6–8 h. Mild liver damage does not have clinical significance on the pharmacokinetics of selinexor. The population pharmacokinetic data from phase I to II studies showed no significant changes in the pharmacokinetics of selinexor in 13 patients with moderate to severe liver damage. The kidney is not the main route of elimination, and no dose adjustment is needed for patients with renal insufficiency. Selinexor is mainly metabolized by cytochrome P450 3A4 (CYP3A4), various UDP-glucuronosyltransferases (UGT), and glutathione S-transferases (GST). Population pharmacokinetic data evaluated the impact of co-medication on selinexor exposure and found that CYP3A4 weak, moderate, and strong inhibitors, CYP3A4 inducers, CYP2D6 inhibitors, CYP2C8 inhibitors, proton pump inhibitors (PPI), H2 receptor blockers, and dexamethasone do not affect the pharmacokinetic data of selinexor (Bader et al., 2021). As of December 2022, in more than 3,200 patients treated with selinexor alone or in combination, there have been few reports of clinically significant drug interactions. Therefore, the co-use of the above drugs does not affect the exposure of selinexor, and no dose adjustment is needed. In addition, preclinical data show that the blood-brain barrier permeability of selinexor in rats and monkeys is 60%–80% (Green et al., 2014).

The above pharmacokinetic characteristics determine the concentration and action time of selinexor in the body, which in turn affects its efficacy. For example, its moderate half-life and clearance rate mean that patients can receive regular treatment without the need for too frequent dose adjustments.

This section will focus on the efficacy and prognosis of selinexor monotherapy for AML. For detailed research data, refer to Table 1. Preclinical trials showed that selinexor was notably toxic to AML cells in NSG mice, reducing human AML cells in the bone marrow and spleen, especially leukemia-initiating cells (LICs), while minimally affecting normal hematopoietic cells, thus preserving normal hematopoiesis (Etchin et al., 2015). Based on these results, a Phase I trial for relapsed/refractory AML (n = 95) was initiated. In a study of 81 patients, the recommended dose of selinexor for treating relapsed/refractory AML was set at 60 mg twice weekly. This dose showed good efficacy and safety, with most adverse events being mild to moderate. Further analysis indicated that patients with lower initial bone marrow blasts were more likely to respond to selinexor, suggesting it may be more suitable for those with MDS or hypoproliferative AML (Garzon et al., 2017). Another Phase II trial recruited R/R AML patients aged over 60 who were ineligible for intensive chemotherapy or bone marrow transplantation. Compared with the investigator’s choice of treatment, selinexor monotherapy demonstrated a significantly higher complete remission/complete remission with incomplete blood count recovery (CR/CRi) rate. Additionally, the study suggested that the activity levels of five proteins might be correlated with selinexor efficacy, and TP53 mutations were associated with an unfavorable prognosis (Sweet et al., 2021). A Phase I study evaluated the safety and efficacy of selinexor monotherapy in patients who underwent allogeneic hematopoietic stem cell transplantation. The findings suggested that long-term selinexor maintenance therapy could be a safe and feasible option for high-risk AML and MDS patients. However, some patients developed acute graft-versus-host disease (aGVHD), which may not have been directly related to selinexor treatment. Additional research is warranted to further explore these findings (Cooperrider et al., 2020).

This part will focus on the choice and clinical outcomes of selinexor combination therapies with various drugs for AML. For specific data, refer to Table 2. Phase I and II clinical studies have explored combining selinexor with chemotherapy for R/R AML. In a Phase II trial, selinexor with cytarabine and idarubicin treated 42 R/R AML patients, achieving CR/CRi in 20, and offering bone marrow transplant opportunities. Low - dose selinexor with chemotherapy also showed good tolerability (Fiedler et al., 2020). Another Phase I trial combined selinexor with the FLAG-ida regimen in young R/R AML patients. Some fatal adverse events occurred. But efficacy was shown with a response rate of 42%. As the MTD wasn’t reached and 100 mg/week of selinexor showed acceptable tolerability and better efficacy, the RP2D was set at 100 mg/week (Martínez Sánchez et al., 2021). This article also analyzed the relationship between gene mutation status and treatment response in AML patients, finding no clear correlation but noting a lower CR/CRi rate in patients with higher bone marrow blasts. It also reported that combining selinexor with the CLAG regimen was safe and effective, serving as a bridge to transplantation for R/R AML patients (Abboud et al., 2019).

Wang et al. (2018) treated 20 newly diagnosed or R/R AML patients with selinexor, high - dose cytarabine and mitoxantrone. No dose - limiting toxicities occurred and the overall response rate was 70%. Also, post - treatment p53 expression in bone marrow blasts increased, while FLT3 and Kit protein levels decreased, indicating a possible post - translational effect. In an American Association for Cancer Research Phase I trial, 21 newly diagnosed high-risk AML patients received selinexor with daunorubicin and cytarabine (7 + 3 regimen). The combination showed promise with a 53% CR/CRi rate and no dose-limiting toxicities during induction, suggesting benefit for high-risk patients and indicating that 80 mg of selinexor with the 7 + 3 regimen is safe (Sweet et al., 2020). For elderly newly diagnosed AML patients, two Phase II randomized controlled studies reported different results. Timothy et al. (Pardee et al., 2020) included patients aged 60 or older. Despite a higher ASXL1 mutation rate in the selinexor group (24% vs. 0), it had higher CR/CRi (85% vs. 43%) and a trend of longer median PFS. However, Janssen et al. (Janssen et al., 2022) studied patients aged 66 or older and found the selinexor-DA regimen led to higher grade 3+ infection rates and early mortality. Most patients reduced/stopped treatment early, with a CR/CRi rate lower than expected. Thus, for elderly or less tolerable AML patients, selinexor dosing needs cautious exploration to balance tolerability and efficacy.

AML patients with abnormal cytoplasmic Topo IIα localization can develop chemoresistance as chemotherapy drugs can’t effectively bind to form DNA cleavage complexes (Gravina et al., 2014; Turner et al., 2009; Turner et al., 2013; Mirski and Cole, 1995; Mutka et al., 2009). To address this, combinations of selinexor and topoisomerase II inhibitors (like etoposide, daunorubicin, mitoxantrone) are being studied. Preclinical trials showed significant improvement in leukemia mouse survival and leukemia burden reduction, indicating therapeutic synergy. Subsequent clinical trials using the MEC regimen (selinexor with etoposide, cytarabine, and mitoxantrone) tested 23 patients, achieving a 33% overall response rate and a median OS of 8.5 months (Bhatnagar et al., 2023), proving its therapeutic potential.

Researchers have explored combining selinexor with hypomethylating agents like decitabine and azacitidine. Decitabine reverses gene silencing from excessive DNA methylation, such as for CDKN1A and FOXO3A (Thépot et al., 2011; Schmelz et al., 2004), and these re - expressed tumor suppressor factors are regulated by XPO1 - mediated nuclear export (Mutka et al., 2009; Turner and Sullivan, 2008). Selinexor, an XPO1 inhibitor, blocks this export, accumulating the factors in the nucleus (Ranganathan et al., 2015). Azacitidine reverses abnormal gene methylation and promotes tumor suppressor gene re - expression (Fakih et al., 2018). Selinexor inhibits XPO1, blocking the nuclear export of tumor suppressor factors and cell cycle regulatory proteins like c - MYC (Fukuda et al., 1997). Together, they significantly downregulate XPO1, eIF4E, and c - MYC, inhibiting AML cell growth and promoting apoptosis (Long et al., 2023) (Figure 3). Preclinical trials showed that in the MV4 - 11 xenograft model, decitabine followed by selinexor increased mouse survival compared to selinexor alone (Ranganathan et al., 2015). In primary AML cells, decitabine pretreatment then selinexor reduced cell viability (Ranganathan et al., 2015). The selinexor - azacitidine combination synergistically reduced AML cell proliferation and promoted apoptosis by upregulating BAX and downregulating BCL - 2 (Long et al., 2023). These findings have been applied in clinical trials. A Phase I trial of decitabine plus selinexor for AML included 25 patients, with an overall response rate of 40%. Using decitabine followed by 60 mg selinexor twice weekly for 2 weeks improved tolerability, showing potential for high - risk AML (Bhatnagar et al., 2019).

There has been progress in combining selinexor with FLT3 inhibitors. Selinexor, a selective nuclear export protein inhibitor (SINE), inhibits XPO1 (CRM1) to block the nuclear export of tumor suppressor proteins like p53, p21, and p27. In FLT3 - mutated AML cells (with ITD or/and TKD mutations), these mutations activate FLT3 and downstream MAPK/AKT signaling, promoting leukemia cell proliferation, inhibiting differentiation, and reducing apoptosis (Zhang et al., 2008) (Figure 4a). Sorafenib, a FLT3 - targeted drug, can inhibit this activation. The combination of selinexor and sorafenib increases the nuclear accumulation of ERK, AKT, NFκB, and FOXO3a, promoting apoptosis and differentiation (Zhang et al., 2018) (Figure 4b). In vitro, this combination promotes differentiation of FLT3 - mutated AML cells into early myeloid cells at low doses with minimal cytotoxicity. Under hypoxia, it partially reverses the protective effect of the hypoxic microenvironment on AML cells and induces synergistic apoptosis. In mouse models, the combination therapy improves mouse survival and reduces leukemia burden (Zhang et al., 2018). A subsequent Phase I study combined FLT3 inhibitors with sorafenib for R/R FLT3 - mutated AML. Among 17 patients, 29% achieved composite complete remission, with a median OS of 4 months. This shows good safety and clinical activity. Among AML patients with FLT3-ITD and/or D835 mutations, 5 (45%) achieved composite complete remission (CRc), and 2 of these patients had a negative FLT3-response at the time of therapy. (Daver et al., 2018).

Based on the published data to date, the dosage (dosage range of 100 mg once a week, 60–80 mg twice a week) and frequency (3 weeks on, 1 week off or 2 weeks on, 2 weeks off) of selinexor vary for AML patients with different tolerance levels and when combined with different intensity drug regimens. The total dose per course is 240–320 mg, and it is necessary to discontinue medication for at least 1 week to ensure recovery from myelosuppression. In addition to the above data, there are several ongoing clinical trials, as detailed in Table 2.

Data from the BOSTON study and the MARCH study show that selinexor has no cumulative toxicity and no organ toxicity, and the current FDA label does not have a black box warning (Grosicki et al., 2020; Qiu et al., 2022). In the monotherapy of AML with selinexor, it has been found that patients will experience certain adverse reactions when treated with selinexor, which can be divided into five categories: hematological, digestive system, systemic, biochemical, and other, with representative symptoms being:

(1) Digestive system adverse reactions: nausea, vomiting, and diarrhea (Garzon et al., 2017).

The above symptoms are the most common in adverse reactions, among which the most frequent is fatigue (60%), and the most frequent grade 3/4 adverse reaction is hematological (32%), so it is necessary to pay high attention to it in treatment and take corresponding measures in a timely manner (Garzon et al., 2017). Fatigue can significantly reduce patients’ quality of life, affecting their ability to perform daily activities and their adherence to treatment, which is more pronounced in elderly AML patients and may further exacerbate their frailty. Hyponatremia may impact patients’ neurological and cardiac functions, increasing the risk of falls, altered mental status, and arrhythmias. In elderly patients, it may lead to more severe consequences, such as cognitive decline and complications related to electrolyte imbalances. Hematologic toxicity, including thrombocytopenia and neutropenia, can lead to an increased risk of bleeding and infections. For elderly AML patients, whose bone marrow function is often already compromised, they may face more severe hematologic toxicity, such as prolonged cytopenias and difficulty in recovery, which may increase treatment-related mortality.

In the past treatment of multiple myeloma (MM) with selinexor, the categories and incidence rates of adverse reactions are similar to those in the treatment of AML, and control measures can be used to intervene in adverse reactions to ensure the prognosis of patients (Gavriatopoulou et al., 2020). Specifically, see Table 3. In terms of control measures, different drugs are mainly used for different symptoms, and supportive nursing measures, such as nutritional support and dose adjustment, can also be taken. The first occurrence of adverse events of selinexor is mainly concentrated within the first two treatment cycles (Nooka et al., 2022), and it is necessary to closely monitor the patient’s blood routine, blood biochemistry, weight, etc., in order to detect and actively handle them in a timely manner. Before medication, it is also necessary to educate patients to recognize the symptoms of selinexor-related adverse reactions and inform patients of the known toxicities, such as anorexia, nausea, and fatigue, which can help patients be prepared to deal with any imminent adverse events.

Considering the mechanism of action of selinexor, its inhibition of XPO1 affects the nucleocytoplasmic transport of various signaling pathways and proteins within the cell, which may partly explain the occurrence of the aforementioned adverse reactions. For instance, inhibition of XPO1 may lead to changes in the intracellular distribution of certain proteins related to cell metabolism, immune regulation, and maintenance of the hematopoietic system, thereby causing issues such as fatigue and hematologic toxicity. In elderly AML patients, due to their declining physiological functions and reduced compensatory capacity, these adverse reactions may be more pronounced and more likely to lead to severe clinical consequences. Therefore, during the treatment process, the patient’s age and physical condition should be fully taken into account to develop personalized treatment plans. Close monitoring of adverse reactions is also essential so that effective intervention measures can be taken in a timely manner to alleviate patient discomfort and improve the safety and tolerability of the treatment.

In addition, other adverse reactions have been found when selinexor is used to treat other diseases, such as constipation, dyspnea, upper respiratory tract infection, etc. (Syed, 2019). Even serious adverse reactions have occurred, such as pneumonia (Gasparetto et al., 2019), lymphocytopenia (Chari et al., 2018; Chen et al., 2018), hyperglycemia (Gasparetto et al., 2019; Chen et al., 2018; Taylor et al., 2018; Gounder et al., 2018), hypocalcemia (Taylor et al., 2018), pulmonary infection (Taylor et al., 2018), hypotension (Taylor et al., 2018), etc., although the incidence rate is low, it still needs attention. The above symptoms still need to be closely monitored and detected in subsequent studies.

In experiments probing the resistance mechanism of selinexor, human fibrosarcoma HT1080 cell lines were subjected to gradually increasing concentrations of KPT-185 (an early analog of selinexor) for up to 10 months. This process yielded SINE-resistant cells. These resistant cells showed more than 100 times lower sensitivity to SINE compounds compared to the parent cells (Crochiere et al., 2015). Compared with the parent cells, the nuclear accumulation of tumor suppressor proteins in the resistant cells was reduced, showing an extended cell cycle (Crochiere et al., 2015); the changes in protein expression were similar, but the changes in the parent cells were more significant (Crochiere et al., 2015); although the drug treatment patterns of transcription changes in the parent and resistant cells were similar, the response in the parent cells was stronger (Crochiere et al., 2015).

Microarray analysis shows that in drug - resistant cells, several key signaling pathways change, including gene expression changes related to cell adhesion, apoptosis, and inflammation (Crochiere et al., 2015). These changes indicate that SINE resistance may be achieved by altering the signaling pathways downstream of XPO1 that are inhibited, among which the NF - κB and AKT - FOXO3 signaling pathways are particularly important.

NF-κB is a key transcription factor regulating cell survival, proliferation, and inflammation. Normally, NF-κB binds to IκB-α and remains inactive in the cytoplasm (Traenckner et al., 1995). When stimulated (e.g., by TNF-α), IκB-α is phosphorylated and degraded, releasing NF-κB to enter the nucleus and activate gene transcription, promoting cell survival and proliferation (Johnson et al., 1999). Selinexor inhibits XPO1, blocking the nuclear export of IκB-α and the NF-κB p65 subunit. This causes their nuclear accumulation and binding, suppressing NF-κB activity, reducing NF-κB-dependent gene transcription, and exerting anti-tumor effects (Kashyap et al., 2016) (Figure 5).

During selinexor therapy, AML cells may develop drug resistance by activating the AKT-FOXO3 signaling pathway. When AKT is activated, it phosphorylates FOXO3, particularly at the S253 site. This phosphorylation causes FOXO3 to bind to 14-3-3 proteins and remain in the cytoplasm, preventing its nuclear translocation (Brunet et al., 1999). As a result, selinexor cannot block the nuclear export of FOXO3 to induce pro-apoptotic transcription, significantly reducing its therapeutic efficacy (Emdal et al., 2022). Figure 6 illustrates this mechanism.

Moreover, Studies indicate that cancer cells may develop resistance to selinexor by upregulating alternative nuclear export pathways. For instance, overexpressing XPOT, a tRNA export protein, can facilitate tRNA nuclear export, bypassing XPO1 blockage. Similarly, upregulating KPNB1, a nuclear transport protein, enables essential nuclear-cytoplasmic molecular transport even in the presence of selinexor. This overexpression helps cancer cells escape selinexor’s inhibitory effects (Cohen et al., 2021). Research on selinexor resistance in CML treatment reveals gene expression changes in resistant cell populations, with distinct RNA expression patterns between resistant and parental cells. These alterations may impair selinexor’s ability to disrupt nuclear-cytoplasmic transport signals, reducing its efficacy. Resistant cells might also upregulate heat shock proteins to counteract selinexor-induced stress and protect cells (Cui et al., 2024). Additionally, a decrease in ferroptosis-related molecule expression may render resistant cells less sensitive to ferroptosis, while increased expression of autophagy-related genes may aid cell survival under selinexor treatment by effectively responding to stress and removing damaged components (Cui et al., 2024). Cell populations with stem cell traits may maintain stemness by upregulating specific genes, potentially contributing to resistance formation (Cui et al., 2024).