The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells

Author(s):Show less -

de Almeida, Luciana Yamamoto ^{[1, 2]} ; Pereira-Martins, Diego A. ^{[1, 2, 3]} ; Weinhaeuser, Isabel ^{[1, 2, 3]} ; Ortiz, Cesar ^{[1, 2]} ; Candido, Larissa A. ^{[1, 2]} ; Lange, Ana Paula ^[2] ; De Abreu, Nayara F. ^[2] ; Mendonza, Silvia E. S. ^{[1, 2]} ; de Deus Wagatsuma, Virginia M. ^{[1, 2]} ; Do Nascimento, Mariane C. ^{[1, 2]} ; Paiva, Helder H. ^{[1, 2]} ; Alves-Paiva, Raquel M. ^{[1, 2]} ; Bonaldo, Camila C. O. M. ^[1] ; Nascimento, Daniele C. ^[4] ; Alves-Filho, Jose C. ^[3] ; Scheucher, Priscila S. ^[2] ; Lima, Ana Silvia G. ^[2] ; Schuringa, Jan Jacob ^[3] ; Ammantuna, Emanuele ^[3] ; Ottone, Tiziana ^{[5, 6, 7]} ; Noguera, Nelida I. ^[5] ; Araujo, Cleide L. ^[1] ; Rego, Eduardo M. ^{[1, 2, 6]}

Affiliation

^[1] Univ Sao Paulo, Ctr Cell Based Therapy, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto - Brazil

^[3] Univ Groningen, Univ Med Ctr Groningen, Canc Res Ctr Groningen, Dept Expt Hematol, Groningen - Netherlands

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[5] Univ Tor Vergata, Dept Biomed & Prevent, Rome - Italy

^[6] Univ Sao Paulo, Fac Med, Lab Invest Med LIM 31 31, Hematol Div, Sao Paulo - Brazil

^[7] IRCCS Neurooncohematol, Santa Lucia Fdn, Rome - Italy

• Document type: Journal article
• Source: FRONTIERS IN ONCOLOGY; v. 11, SEP 28 2021.
• Web of Science Citations: 0

Abstract

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.</p> (AU)

• FAPESP's process: 17/00775-3 - Study of the epidermal growth factor receptor inhibitor gefitinib in acute myeloid leukemia cell line
• Grantee: Nayara Ferreira de Abreu
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 16/17521-1 - Analysis of bone morrow mesenchymal cells from patients with acute myeloid leukemia and from healthy subjects in an assay of coculture with leukemic blats
• Grantee: Mariane Cristina Do Nascimento
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 10/16966-3 - Identification and functional characterization of leukemic stem cells in human acute promyelocytic leukemia
• Grantee: Helder Henrique Paiva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/09228-0 - Detection and functional analysis of Tumor-Associated Macrophages (TAM) in a transgenic model of acute promyelocytic leukemia (APL).
• Grantee: Isabel Weinhauser
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/23117-1 - Evaluation of TP53/TP73 pathway in engraftment of acute promyelocytic leukemia cells in xenotransplantation model
• Grantee: Diego Antonio Pereira Martins
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/11817-8 - Aditional mutations to the PML-RARa gene rearrangement by transcriptome, whole-exome and metilome analysis in Acute Promyelocytic Leukemia samples obtained at diagnosis, molecular remission and relapse time
• Grantee: Virgínia Mara de Deus Wagatsuma
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/18313-0 - Mechanisms of development of liver cirrhosis by CCl4 and schistosomiasis in Tert-/- knockout and DKC1m hypomorphic transgenic mice
• Grantee: Raquel de Melo Alves Paiva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/17111-4 - In vivo study of the role of CCAAT Enhancer binding protein alpha (CEBPA)gene hipoexpression in the leukemogenesis induced by the CALM/AF10 hybrid protein.
• Grantee: Ana Paula Alencar de Lima Lange
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/02713-2 - Effects of erlotinib and gefitinib therapy in combination with all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: in vitro, ex vivo and murine experimental model studies.
• Grantee: Luciana Yamamoto de Almeida
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/08430-5 - Detection of TP73 gene transcripts in Acute Promyelocytic Leukemia and their impact in prognosis and therapeutics response
• Grantee: César Alexander Ortiz Rojas
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)