The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells
In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinica...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.686445/full |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Luciana Yamamoto de Almeida Luciana Yamamoto de Almeida Diego A. Pereira-Martins Diego A. Pereira-Martins Diego A. Pereira-Martins Isabel Weinhäuser Isabel Weinhäuser Isabel Weinhäuser César Ortiz César Ortiz Larissa A. Cândido Larissa A. Cândido Ana Paula Lange Nayara F. De Abreu Sílvia E. S. Mendonza Sílvia E. S. Mendonza Virgínia M. de Deus Wagatsuma Virgínia M. de Deus Wagatsuma Mariane C. Do Nascimento Mariane C. Do Nascimento Helder H. Paiva Helder H. Paiva Raquel M. Alves-Paiva Raquel M. Alves-Paiva Camila C. O. M. Bonaldo Daniele C. Nascimento José C. Alves-Filho Priscila S. Scheucher Ana Sílvia G. Lima Jan Jacob Schuringa Emanuele Ammantuna Tiziana Ottone Tiziana Ottone Tiziana Ottone Nelida I. Noguera Cleide L. Araujo Eduardo M. Rego Eduardo M. Rego Eduardo M. Rego |
| spellingShingle |
Luciana Yamamoto de Almeida Luciana Yamamoto de Almeida Diego A. Pereira-Martins Diego A. Pereira-Martins Diego A. Pereira-Martins Isabel Weinhäuser Isabel Weinhäuser Isabel Weinhäuser César Ortiz César Ortiz Larissa A. Cândido Larissa A. Cândido Ana Paula Lange Nayara F. De Abreu Sílvia E. S. Mendonza Sílvia E. S. Mendonza Virgínia M. de Deus Wagatsuma Virgínia M. de Deus Wagatsuma Mariane C. Do Nascimento Mariane C. Do Nascimento Helder H. Paiva Helder H. Paiva Raquel M. Alves-Paiva Raquel M. Alves-Paiva Camila C. O. M. Bonaldo Daniele C. Nascimento José C. Alves-Filho Priscila S. Scheucher Ana Sílvia G. Lima Jan Jacob Schuringa Emanuele Ammantuna Tiziana Ottone Tiziana Ottone Tiziana Ottone Nelida I. Noguera Cleide L. Araujo Eduardo M. Rego Eduardo M. Rego Eduardo M. Rego The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells Frontiers in Oncology epidermal growth factor receptor (EGFR) erlotinib gefitinib all-trans retinoic acid (ATRA) acute promyelocytic leukemia (APL) ATRA-resistance |
| author_facet |
Luciana Yamamoto de Almeida Luciana Yamamoto de Almeida Diego A. Pereira-Martins Diego A. Pereira-Martins Diego A. Pereira-Martins Isabel Weinhäuser Isabel Weinhäuser Isabel Weinhäuser César Ortiz César Ortiz Larissa A. Cândido Larissa A. Cândido Ana Paula Lange Nayara F. De Abreu Sílvia E. S. Mendonza Sílvia E. S. Mendonza Virgínia M. de Deus Wagatsuma Virgínia M. de Deus Wagatsuma Mariane C. Do Nascimento Mariane C. Do Nascimento Helder H. Paiva Helder H. Paiva Raquel M. Alves-Paiva Raquel M. Alves-Paiva Camila C. O. M. Bonaldo Daniele C. Nascimento José C. Alves-Filho Priscila S. Scheucher Ana Sílvia G. Lima Jan Jacob Schuringa Emanuele Ammantuna Tiziana Ottone Tiziana Ottone Tiziana Ottone Nelida I. Noguera Cleide L. Araujo Eduardo M. Rego Eduardo M. Rego Eduardo M. Rego |
| author_sort |
Luciana Yamamoto de Almeida |
| title |
The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells |
| title_short |
The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells |
| title_full |
The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells |
| title_fullStr |
The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells |
| title_full_unstemmed |
The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells |
| title_sort |
combination of gefitinib with atra and ato induces myeloid differentiation in acute promyelocytic leukemia resistant cells |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Oncology |
| issn |
2234-943X |
| publishDate |
2021-09-01 |
| description |
In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients. |
| topic |
epidermal growth factor receptor (EGFR) erlotinib gefitinib all-trans retinoic acid (ATRA) acute promyelocytic leukemia (APL) ATRA-resistance |
| url |
https://www.frontiersin.org/articles/10.3389/fonc.2021.686445/full |
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doaj-7571ff921fee43699747c4b3cd44329e2021-09-28T06:48:54ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-09-011110.3389/fonc.2021.686445686445The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant CellsLuciana Yamamoto de Almeida0Luciana Yamamoto de Almeida1Diego A. Pereira-Martins2Diego A. Pereira-Martins3Diego A. Pereira-Martins4Isabel Weinhäuser5Isabel Weinhäuser6Isabel Weinhäuser7César Ortiz8César Ortiz9Larissa A. Cândido10Larissa A. Cândido11Ana Paula Lange12Nayara F. De Abreu13Sílvia E. S. Mendonza14Sílvia E. S. Mendonza15Virgínia M. de Deus Wagatsuma16Virgínia M. de Deus Wagatsuma17Mariane C. Do Nascimento18Mariane C. Do Nascimento19Helder H. Paiva20Helder H. Paiva21Raquel M. Alves-Paiva22Raquel M. Alves-Paiva23Camila C. O. M. Bonaldo24Daniele C. Nascimento25José C. Alves-Filho26Priscila S. Scheucher27Ana Sílvia G. Lima28Jan Jacob Schuringa29Emanuele Ammantuna30Tiziana Ottone31Tiziana Ottone32Tiziana Ottone33Nelida I. Noguera34Cleide L. Araujo35Eduardo M. Rego36Eduardo M. Rego37Eduardo M. Rego38Department of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Pharmacology, University of Sao Paulo, Ribeirao Preto Medical School, Ribeirao Preto, BrazilDepartment of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilDepartment of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsDepartment of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, NetherlandsDepartment of Biomedicine and Prevention, University of Tor Vergata, Rome, ItalySanta Lucia Foundation, I.R.C.C.S., Neuro-Oncohematology, Rome, ItalyHematology Division, Laboratórios de Investigação Médica 31 (LIM 31), Faculdade de Medicina, University of Sao Paulo, Sao Paulo, BrazilDepartment of Biomedicine and Prevention, University of Tor Vergata, Rome, ItalyCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, BrazilCenter for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, BrazilHematology Division, Laboratórios de Investigação Médica 31 (LIM 31), Faculdade de Medicina, University of Sao Paulo, Sao Paulo, BrazilIn approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.https://www.frontiersin.org/articles/10.3389/fonc.2021.686445/fullepidermal growth factor receptor (EGFR)erlotinibgefitiniball-trans retinoic acid (ATRA)acute promyelocytic leukemia (APL)ATRA-resistance |