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XPO1 Inhibition using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia by Targeting DNA Repair and

Parvathi Ranganathan1, Trinayan Kashyap2, Xueyan Yu1

  • 1The Ohio State University, Columbus, Ohio.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 1, 2016
PubMed
Abstract

Insights

Combining selinexor with topoisomerase II inhibitors shows therapeutic synergy in acute myeloid leukemia (AML) models. This combination therapy, including idarubicin, significantly improves survival in AML mice, offering a promising new treatment strategy.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) is molecularly complex, often requiring combination therapy for effective treatment.
  • Selinexor, a selective XPO1 inhibitor, is under investigation for AML.
  • Monotherapy with selinexor may be insufficient to overcome AML's complexity.

Purpose of the Study:

  • To investigate the potential of combining selinexor with topoisomerase (Topo) II inhibitors for enhanced anti-leukemic effects in AML.
  • To evaluate the synergistic efficacy of selinexor and Topo II inhibitors in preclinical AML models.

Main Methods:

  • Evaluated combinatorial drug treatment with Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor.
  • Utilized established cellular and animal models of AML, including a xenograft MV4-11 mouse model.

Main Results:

  • Concomitant treatment with selinexor and Topo II inhibitors demonstrated therapeutic synergy in AML cell lines and patient samples.
  • Treatment with selinexor and idarubicin significantly prolonged survival in a xenograft AML mouse model compared to single-agent therapies.
  • Selinexor induced nuclear retention of Topo IIα in a subset of AML patients, enhancing idarubicin sensitivity.

Conclusions:

  • Aberrant nuclear export of Topo IIα is a mechanism of drug resistance in cancer.
  • Selinexor treatment leads to nuclear retention of Topo IIα, increasing sensitivity to idarubicin in AML.
  • Selinexor reduces DNA damage repair genes (Rad51, Chk1) via c-MYC, inhibiting homologous recombination repair and sensitizing cells to Topo II inhibitors.
  • Preclinical data support further clinical investigation of selinexor and Topo II inhibitor combinations for AML treatment.

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