Abstract
Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.
Highlights
XPO1 is a member of the Karyopherin β superfamily of nuclear transport proteins that facilitates the nuclear export of RNA [1] and cargo proteins with leucine-rich nuclear export signals (NESs) by forming a ternary complex with Ran-GTP [2]
Most cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM
The alveolar soft part sarcoma (ASPS) lines, ASPS-KY and ASPS-1, were exceptionally resistant to selinexor with IC50 greater than 2 μM. Some cell lines, such as LPS12, showed shallow curves; this is likely due to their slow growth rates since the cell viability curves shifted deeper with almost identical relative IC50s when treated for seven days
Summary
XPO1 is a member of the Karyopherin β superfamily of nuclear transport proteins that facilitates the nuclear export of RNA [1] and cargo proteins with leucine-rich nuclear export signals (NESs) by forming a ternary complex with Ran-GTP [2]. These NES-bearing cargo proteins include tumor suppressors such as p53 [3, 4], RB [5], and APC [6], cell cycle regulators such as p21 [7, 8], and many others [9,10,11]. Prior preclinical and clinical studies have demonstrated activity in certain solid tumors [24,25,26,27,28] as well as in hematologic malignancies [29,30,31] with induction of cell cycle arrest or apoptosis and nuclear accumulation of XPO1 cargo tumor suppressor proteins
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