de Almeida Luciana Yamamoto, Pereira-Martins Diego A, Weinhäuser Isabel, Ortiz César, Cândido Larissa A, Lange Ana Paula, De Abreu Nayara F, Mendonza Sílvia E S, de Deus Wagatsuma Virgínia M, Do Nascimento Mariane C, Paiva Helder H, Alves-Paiva Raquel M, Bonaldo Camila C O M, Nascimento Daniele C, Alves-Filho José C, Scheucher Priscila S, Lima Ana Sílvia G, Schuringa Jan Jacob, Ammantuna Emanuele, Ottone Tiziana, Noguera Nelida I, Araujo Cleide L, Rego Eduardo M
Department of Medical Images, Hematology, and Clinical Oncology, University of Sao Paulo at Ribeirao Preto Medical School, Ribeirao Preto, Brazil.
Center for Cell-Based Therapy, University of Sao Paulo, Ribeirao Preto, Brazil.
Front Oncol. 2021 Sep 28;11:686445. doi: 10.3389/fonc.2021.686445. eCollection 2021.
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 . 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 and 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. , 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. , 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.
据报道，在大约15%的急性髓系白血病（AML）患者中，与健康的CD34样本相比，总EGFR蛋白和磷酸化EGFR蛋白有所增加。然而，尚不清楚这部分患者是否会从EGFR信号通路的药理学抑制中获益。对AML细胞的临床前研究提供了证据，表明EGFR抑制剂与全反式维甲酸（ATRA）或三氧化二砷（ATO）联合使用具有促分化益处。尽管ATRA和ATO在治疗急性早幼粒细胞白血病（APL）患者方面取得了成功，但在5%-10%的病例中观察到了治疗相关耐药性，这表明这些患者显然需要新的治疗策略。在此背景下，EGFR酪氨酸激酶抑制剂在APL中的功能作用从未得到评估。在这里，我们利用几种APL模型，对原代样本中的EGFR通路以及功能和进行了研究。我们观察到，APL患者的原始细胞中分别有28%和19%表达总EGFR和磷酸化EGFR（Tyr992），而健康的CD34样本中未表达。有趣的是，APL血浆样本中表皮生长因子（EGF）的表达低于健康对照。在29%的APL患者诊断时检测到EGFR配体双调蛋白（AREG），但对照样本中未检测到。用EGFR抑制剂吉非替尼（ZD1839）治疗可降低NB4（对ATRA敏感）和NB4-R2（对ATRA耐药）细胞的增殖和存活率。此外，吉非替尼与ATRA和ATO联合使用可促进对ATRA和ATO耐药的APL细胞的髓系细胞分化。在同基因移植模型中，与用吉非替尼或赋形剂治疗的白血病小鼠相比，吉非替尼与ATRA联合使用可延长生存期，不过与单独使用ATRA治疗相比，生存期的延长未达到统计学差异。我们的结果表明，吉非替尼是一种潜在的辅助药物，可减轻APL细胞对ATRA和ATO的耐药性。因此，我们的数据表明，重新利用美国食品药品监督管理局（FDA）批准的酪氨酸激酶抑制剂可为联合治疗提供新的视角，以克服APL患者的耐药性。
