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A method for quantification of exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds

Marsha L Crochiere1, Erkan Baloglu1, Boris Klebanov1

  • 1All authors are current or former employees of Karyopharm Therapeutics Inc., Newton, MA, 02459 U.S.A.

Oncotarget
|December 15, 2015
PubMed

Insights

Selective Inhibitor of Nuclear Export (SINE) compounds target Exportin 1 (XPO1) to kill cancer cells. Cancer cell response to selinexor depends on downstream pathway modulation, not solely XPO1 occupancy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Selective Inhibitor of Nuclear Export (SINE) compounds target Exportin 1 (XPO1/CRM1) via covalent binding at Cys528.
  • Selinexor is a lead SINE compound investigated in clinical trials for advanced cancers.
  • Understanding the drug-target engagement of selinexor and XPO1 is crucial for cancer treatment efficacy.

Purpose of the Study:

  • To develop a quantitative assay to measure XPO1 occupancy by SINE compounds.
  • To investigate the relationship between selinexor-XPO1 interaction and cancer cell response.
  • To determine if cancer cell resistance is linked to XPO1 target engagement.

Main Methods:

  • Developed a quantitative XPO1 occupancy assay using biotinylated leptomycin B (b-LMB) as a tool compound.
  • Quantitated XPO1 binding in various cell models (adherent, suspension, PBMCs) and in vivo mouse models.
  • Assessed selinexor sensitivity and resistance in a panel of cancer cell lines.

Main Results:

  • Selinexor demonstrated sustained XPO1 binding for at least 72 hours in vitro and in vivo.
  • Cancer cell resistance to selinexor was not explained by reduced XPO1 occupancy.
  • XPO1 inhibition correlated with selinexor pharmacokinetics, but downstream effects dictated cell response.

Conclusions:

  • Selinexor effectively engages its target XPO1, with sustained binding observed.
  • Cancer cell responsiveness to selinexor is determined by the modulation of pathways downstream of XPO1.
  • The study highlights the importance of downstream signaling in SINE compound efficacy.
Keywords:
cancerexportoccupancyresistanceselinexor

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