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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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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. |
format | Online Article Text |
id | pubmed-6387953 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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