AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.

Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ(1) derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ(1) resistance are incompletely und...

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Autores principales:	David B Rosen, Kimberly H Harrington, James A Cordeiro, Ling Y Leung, Santosh Putta, Norman Lacayo, George S Laszlo, Chelsea J Gudgeon, Donna E Hogge, Rachael E Hawtin, Alessandra Cesano, Roland B Walter
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cdee93bca07145d3b4ee0e020e486f40
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spelling	oai:doaj.org-article:cdee93bca07145d3b4ee0e020e486f402021-11-18T08:02:18ZAKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.1932-620310.1371/journal.pone.0053518https://doaj.org/article/cdee93bca07145d3b4ee0e020e486f402013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23320091/?tool=EBIhttps://doaj.org/toc/1932-6203Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ(1) derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ(1) resistance are incompletely understood, we herein used flow cytometry-based single cell network profiling (SCNP) assays to study cellular responses of primary human AML cells to GO. Our data indicate that the extent of DNA damage is quantitatively impacted by CD33 expression and drug efflux activity. However, although DNA damage is required for GO-induced cytotoxicity, it is not sufficient for effective cell kill, suggesting that downstream anti-apoptotic pathways may function as relevant resistance mechanisms. Supporting this notion, we found activated PI3K/AKT signaling to be associated with GO resistance in vitro in primary AML cells. Consistently, the investigational AKT inhibitor MK-2206 significantly sensitized various human AML cells to GO or free calicheamicin-γ(1) with particularly pronounced effects in otherwise GO or free calicheamicin-γ(1)-resistant cells. Likewise, MK-2206 also sensitized primary AML cells to calicheamicin-γ(1). Together, our findings illustrate the capacity of SCNP assays to discover chemotherapy-related biological pathways and signaling networks relevant to GO-induced genotoxic stress. The identification of AKT signaling as being associated with GO resistance in vitro may provide a novel approach to improve the in vivo efficacy of GO/calicheamicin-γ(1) and, by extrapolation, other DNA damage-based therapeutics.David B RosenKimberly H HarringtonJames A CordeiroLing Y LeungSantosh PuttaNorman LacayoGeorge S LaszloChelsea J GudgeonDonna E HoggeRachael E HawtinAlessandra CesanoRoland B WalterPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e53518 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David B Rosen Kimberly H Harrington James A Cordeiro Ling Y Leung Santosh Putta Norman Lacayo George S Laszlo Chelsea J Gudgeon Donna E Hogge Rachael E Hawtin Alessandra Cesano Roland B Walter AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.
description	Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ(1) derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ(1) resistance are incompletely understood, we herein used flow cytometry-based single cell network profiling (SCNP) assays to study cellular responses of primary human AML cells to GO. Our data indicate that the extent of DNA damage is quantitatively impacted by CD33 expression and drug efflux activity. However, although DNA damage is required for GO-induced cytotoxicity, it is not sufficient for effective cell kill, suggesting that downstream anti-apoptotic pathways may function as relevant resistance mechanisms. Supporting this notion, we found activated PI3K/AKT signaling to be associated with GO resistance in vitro in primary AML cells. Consistently, the investigational AKT inhibitor MK-2206 significantly sensitized various human AML cells to GO or free calicheamicin-γ(1) with particularly pronounced effects in otherwise GO or free calicheamicin-γ(1)-resistant cells. Likewise, MK-2206 also sensitized primary AML cells to calicheamicin-γ(1). Together, our findings illustrate the capacity of SCNP assays to discover chemotherapy-related biological pathways and signaling networks relevant to GO-induced genotoxic stress. The identification of AKT signaling as being associated with GO resistance in vitro may provide a novel approach to improve the in vivo efficacy of GO/calicheamicin-γ(1) and, by extrapolation, other DNA damage-based therapeutics.
format	article
author	David B Rosen Kimberly H Harrington James A Cordeiro Ling Y Leung Santosh Putta Norman Lacayo George S Laszlo Chelsea J Gudgeon Donna E Hogge Rachael E Hawtin Alessandra Cesano Roland B Walter
author_facet	David B Rosen Kimberly H Harrington James A Cordeiro Ling Y Leung Santosh Putta Norman Lacayo George S Laszlo Chelsea J Gudgeon Donna E Hogge Rachael E Hawtin Alessandra Cesano Roland B Walter
author_sort	David B Rosen
title	AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.
title_short	AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.
title_full	AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.
title_fullStr	AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.
title_full_unstemmed	AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.
title_sort	akt signaling as a novel factor associated with in vitro resistance of human aml to gemtuzumab ozogamicin.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/cdee93bca07145d3b4ee0e020e486f40
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AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin.

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