1. Academic Validation
  2. Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia

Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia

  • Cancers (Basel). 2020 Jun 14;12(6):1574. doi: 10.3390/cancers12061574.
Lindsey T Brinton 1 Steven Sher 1 Katie Williams 1 Daniel Canfield 1 Shelley Orwick 1 Ronni Wasmuth 1 Casey Cempre 1 Jordan Skinner 1 Amy Lehman 2 James S Blachly 1 3 4 John C Byrd 1 3 5 6 Rosa Lapalombella 1 3
Affiliations

Affiliations

  • 1 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
  • 2 Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA.
  • 3 Leukemia Research Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH 43210, USA.
  • 4 Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
  • 5 College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
  • 6 College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.
Abstract

Acute myeloid leukemia (AML) is a hematopoietic stem-cell-derived leukemia with often successive derived driver mutations. Late onset acquisition of internal tandem duplication in FLT3 (FLT3-ITD) at a high variant allele frequency often contributes to full transformation to a highly proliferative, rapidly progressive disease with poor outcome. The FLT3-ITD mutation is targetable with approved FLT3 small molecule inhibitors, including midostaurin and gilteritinib. However, outside of patients receiving allogeneic transplant, most patients fail to respond or relapse, suggesting alternative approaches of therapy will be required. We employed genome-wide pooled CRISPR knockout screening as a method for large-scale identification of targets whose knockout produces a phenotypic effect that enhances the antitumor properties of FLT3 inhibitors. Among the candidate targets we identified the effect of XPO1 knockout to be synergistic with midostaurin treatment. Next, we validated the genetic finding with pharmacologic combination of the slowly reversible XPO1 inhibitor selinexor with midostaurin and gilteritinib in FLT3-ITD AML cell lines and primary patient samples. Lastly, we demonstrated improved survival with either combination therapy compared to its monotherapy components in an aggressive AML murine model, supporting further evaluation and rapid clinical translation of this combination strategy.

Keywords

AML; CRISPR-Cas9 screening; FLT3; XPO1; synergism.

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