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Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53

Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to...

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Autores principales: Tirrò, Elena, Massimino, Michele, Romano, Chiara, Pennisi, Maria Stella, Stella, Stefania, Vitale, Silvia Rita, Fidilio, Annamaria, Manzella, Livia, Parrinello, Nunziatina Laura, Stagno, Fabio, Palumbo, Giuseppe Alberto, La Cava, Piera, Romano, Alessandra, Di Raimondo, Francesco, Vigneri, Paolo G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387953/
https://www.ncbi.nlm.nih.gov/pubmed/30834235
http://dx.doi.org/10.3389/fonc.2019.00057
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author Tirrò, Elena
Massimino, Michele
Romano, Chiara
Pennisi, Maria Stella
Stella, Stefania
Vitale, Silvia Rita
Fidilio, Annamaria
Manzella, Livia
Parrinello, Nunziatina Laura
Stagno, Fabio
Palumbo, Giuseppe Alberto
La Cava, Piera
Romano, Alessandra
Di Raimondo, Francesco
Vigneri, Paolo G.
author_facet Tirrò, Elena
Massimino, Michele
Romano, Chiara
Pennisi, Maria Stella
Stella, Stefania
Vitale, Silvia Rita
Fidilio, Annamaria
Manzella, Livia
Parrinello, Nunziatina Laura
Stagno, Fabio
Palumbo, Giuseppe Alberto
La Cava, Piera
Romano, Alessandra
Di Raimondo, Francesco
Vigneri, Paolo G.
author_sort Tirrò, Elena
collection PubMed
description Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2/M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibitor UCN-01, we successfully abrogated IO-induced G2/M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC(50) values. Likewise, overexpression of an inducible wild-type p53 in cells natively presenting a mutant protein decreased their IC(50) for IO. These results were also confirmed in primary CD22-positive cells derived from B-ALL patients at diagnosis and from patients with r/r B-ALL. Furthermore, co-treatment with IO and UCN-01 significantly increased cell death in primary cells expressing mutant p53. In summary, our findings suggest that p53 status may represent a biomarker predictive of IO efficacy in patients diagnosed with CD22-positive malignancies.
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spelling pubmed-63879532019-03-04 Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53 Tirrò, Elena Massimino, Michele Romano, Chiara Pennisi, Maria Stella Stella, Stefania Vitale, Silvia Rita Fidilio, Annamaria Manzella, Livia Parrinello, Nunziatina Laura Stagno, Fabio Palumbo, Giuseppe Alberto La Cava, Piera Romano, Alessandra Di Raimondo, Francesco Vigneri, Paolo G. Front Oncol Oncology Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2/M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibitor UCN-01, we successfully abrogated IO-induced G2/M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC(50) values. Likewise, overexpression of an inducible wild-type p53 in cells natively presenting a mutant protein decreased their IC(50) for IO. These results were also confirmed in primary CD22-positive cells derived from B-ALL patients at diagnosis and from patients with r/r B-ALL. Furthermore, co-treatment with IO and UCN-01 significantly increased cell death in primary cells expressing mutant p53. In summary, our findings suggest that p53 status may represent a biomarker predictive of IO efficacy in patients diagnosed with CD22-positive malignancies. Frontiers Media S.A. 2019-02-18 /pmc/articles/PMC6387953/ /pubmed/30834235 http://dx.doi.org/10.3389/fonc.2019.00057 Text en Copyright © 2019 Tirrò, Massimino, Romano, Pennisi, Stella, Vitale, Fidilio, Manzella, Parrinello, Stagno, Palumbo, La Cava, Romano, Di Raimondo and Vigneri. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Tirrò, Elena
Massimino, Michele
Romano, Chiara
Pennisi, Maria Stella
Stella, Stefania
Vitale, Silvia Rita
Fidilio, Annamaria
Manzella, Livia
Parrinello, Nunziatina Laura
Stagno, Fabio
Palumbo, Giuseppe Alberto
La Cava, Piera
Romano, Alessandra
Di Raimondo, Francesco
Vigneri, Paolo G.
Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53
title Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53
title_full Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53
title_fullStr Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53
title_full_unstemmed Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53
title_short Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53
title_sort chk1 inhibition restores inotuzumab ozogamicin citotoxicity in cd22-positive cells expressing mutant p53
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387953/
https://www.ncbi.nlm.nih.gov/pubmed/30834235
http://dx.doi.org/10.3389/fonc.2019.00057
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