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424 Malakar et al. | Journal of Clinical and Translational Research 2023; 9(6): 423-432
response and prognosis [3]. On the other hand, ALL predominantly explored. Gaining insights into selinexor’s mechanism of action
target lymphoblasts, immature white blood cells belonging to the within the context of ALL is crucial for optimizing its efficacy as
lymphoid lineage [4]. In the United States, approximately 6,540 a standalone treatment or in synergy with combination therapies.
new cases of ALL were diagnosed in the year 2023, resulting in In this review, we discuss the possible targets of selinexor in
over 1,390 deaths from the disease (American Cancer Society). ALL, such as mTOR signaling, glucose metabolism, alternative
ALL is characterized by specific genetic abnormalities, including splicing, long non-coding RNA expression, and autophagy, all
chromosomal translocations such as the Philadelphia chromosome of which may play critical roles in determining the pathogenesis
(Ph+), which is associated with a more adverse prognosis [3,4]. of the disease and the effectiveness of chemotherapy. We have
Among the spectrum of ALL, a distinctive subtype called B-cell provided the descriptions of clinical and preclinical studies of
precursor ALL (B-pre-ALL) emerges. Moreover, this subtype selinexor in various cancers (Tables 1 and 2).
specifically targets B-cell precursors or immature B-lymphocytes,
rendering it the most widespread variant of ALL, particularly 2. mTOR
prevalent among children [4,5]. In managing both AML and mTOR is a conserved serine/threonine kinase that belongs to
ALL, various therapeutic strategies are employed, including the PI3K-related kinase family and exists in two distinct signaling
chemotherapy, immunotherapy, targeted therapy (like monoclonal complexes known as mTORC1 and mTORC2 [23,24]. mTORC1
antibodies), or allogeneic stem cell transplantation [6]. Due to a plays a significant role in mRNA translation and protein synthesis,
higher tendency of central nervous system (CNS) involvement in whereas mTORC2 substantially contributes to cell survival and
ALL as compared to AML, treatments with a specific focus on the migration [23,24]. The mTOR pathway occupies a central position
CNS (such as intrathecal chemotherapy or cranial radiation) are in sensing environmental cues and monitoring virtually all facets
frequently integrated into ALL treatment protocols [7]. Despite of metabolism, spanning from the cellular to the organismal
advancements in the therapeutic process, relapsed cases of ALL level [25]. Dysregulated mTOR signaling is linked to cancer and
remain a significant challenge, exhibiting unfavorable prognoses. diabetes progression, along with the aging process [26]. Given
Thus, a critical need exists to develop effective therapies for that the activation of the PI3K/Akt/mTOR network is frequently
treating relapsed ALL and to explore novel combinatorial linked to a poor prognosis and chemoresistance in ALL, there
therapeutic regimens with chemotherapy to enhance outcomes in remains an ongoing demand to identify novel inhibitors for the
newly diagnosed patients [8]. Elucidating the underlying molecular effective treatment of this disease. This is particularly relevant
mechanisms that contribute to de novo or acquired drug resistance given the mounting evidence indicating mTOR dysregulation’s
presents a ubiquitous obstacle in cancer therapeutics [9]. This association with metastatic potential, cell proliferation, and
underscores the imperative to explore novel targeted therapeutic angiogenesis. [27,28]. Moreover, B-pre-ALL is characterized by
strategies, specifically directed toward ALL [10]. Noticeably, constitutive activation of the PI3K/Akt/mTOR network, which is
selective inhibitors of nuclear export (SINE) are emerging as a known to significantly impact cell growth and survival [29].
potential therapeutic approach to overcome drug resistance in the
context of AML [11]. The application of selinexor to AML cell lines led to
Selinexor, an inhibitor of nuclear export, was recently the reduction of mTOR activity [13]. Moreover, selinexor
demonstrated to bind reversibly and inhibit the nuclear export demonstrates synergistic effects with dexamethasone to
protein exportin-1 (XPO1), leading to the accumulation of suppress mTORC1 signaling and promote cell death in multiple
cargo proteins inside the cell nucleus [12]. Selinexor exerts its myeloma [16] (Table 2). Consequently, investigating the impact
effects on multiple myeloma by inhibiting nuclear factor kappa of selinexor treatment on mTOR signaling in the context of
B (NF-kB) signaling, reactivating various tumor suppressor ALL holds significant therapeutic importance (Figure 1A). This
proteins, and reducing c-myc levels [13,14]. A recent study has endeavor is pivotal for assessing the efficacy of selinexor in ALL
indicated that selinexor treatment led to the downregulation treatments.
of the mammalian (or mechanistic) target of rapamycin 3. Reprogrammed Glucose Metabolism in Cancer
(mTOR) signaling pathway in sensitive and resistant AML cell
lines [13]. Selinexor exhibited synergistic antimyeloma effects Aberrant glucose metabolism has emerged as a major type
when combined with glucocorticoids, proteasome inhibitors (PIs), of metabolic reprogramming in cancer, discovered by Otto
and immunomodulators in preclinical studies [14,15]. Notably, Warburg in the late 1920s [30]. The uncontrolled proliferation of
the combination of selinexor and dexamethasone (DEX) has cancer cells induces a heightened demand for nutrients, creating
received approval in the United States for treating patients with an environment of limited nutrient availability. In response to
penta-refractory multiple myeloma [16]. Moreover, the selinexor- this increased nutritional stress, cancer cells undergo metabolic
bortezomib-dexamethasone combination has also been approved adaptations. Cancer cells exhibit a preference for utilizing
for patients who have received ≥1 prior therapy in multiple glycolysis as their primary pathway for glucose metabolism
myeloma patients [16]. The clinical trial of selinexor, either as even in oxygen-abundant conditions, rather than relying on
a monotherapy or in combination, for AML patients has been the more efficient mitochondrial oxidative phosphorylation
shown in Table 1. However, the impact of selinexor treatment on for ATP production [30,31]. Moreover, the cancer cells exploit
ALL as a single agent or in combination therapies has not been elevated levels of glucose as a primary carbon source to fuel
DOI: http://dx.doi.org/10.18053/jctres.09.202306.23-00088