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

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, r...

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Autores principales: Brinton, Lindsey T., Sher, Steven, Williams, Katie, Canfield, Daniel, Orwick, Shelley, Wasmuth, Ronni, Cempre, Casey, Skinner, Jordan, Lehman, Amy, Blachly, James S., Byrd, John C., Lapalombella, Rosa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352446/
https://www.ncbi.nlm.nih.gov/pubmed/32545904
http://dx.doi.org/10.3390/cancers12061574
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author Brinton, Lindsey T.
Sher, Steven
Williams, Katie
Canfield, Daniel
Orwick, Shelley
Wasmuth, Ronni
Cempre, Casey
Skinner, Jordan
Lehman, Amy
Blachly, James S.
Byrd, John C.
Lapalombella, Rosa
author_facet Brinton, Lindsey T.
Sher, Steven
Williams, Katie
Canfield, Daniel
Orwick, Shelley
Wasmuth, Ronni
Cempre, Casey
Skinner, Jordan
Lehman, Amy
Blachly, James S.
Byrd, John C.
Lapalombella, Rosa
author_sort Brinton, Lindsey T.
collection PubMed
description 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.
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spelling pubmed-73524462020-07-15 Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia Brinton, Lindsey T. Sher, Steven Williams, Katie Canfield, Daniel Orwick, Shelley Wasmuth, Ronni Cempre, Casey Skinner, Jordan Lehman, Amy Blachly, James S. Byrd, John C. Lapalombella, Rosa Cancers (Basel) Article 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. MDPI 2020-06-14 /pmc/articles/PMC7352446/ /pubmed/32545904 http://dx.doi.org/10.3390/cancers12061574 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brinton, Lindsey T.
Sher, Steven
Williams, Katie
Canfield, Daniel
Orwick, Shelley
Wasmuth, Ronni
Cempre, Casey
Skinner, Jordan
Lehman, Amy
Blachly, James S.
Byrd, John C.
Lapalombella, Rosa
Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
title Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
title_full Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
title_fullStr Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
title_full_unstemmed Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
title_short Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
title_sort cotargeting of xpo1 enhances the antileukemic activity of midostaurin and gilteritinib in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352446/
https://www.ncbi.nlm.nih.gov/pubmed/32545904
http://dx.doi.org/10.3390/cancers12061574
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