耐药性:发现了治疗B细胞淋巴瘤的一个新的关键机制

诸平

据瑞士意大利语区大学（University of Italian Switzerland）也称为瑞士提契诺大学（Università della Svizzera italiana简称USI）2024年2月22日提供的消息，由肿瘤学研究所(Institute of Oncology Research简称IOR，隶属于USI和Bios+成员)的弗朗西斯科·贝尔托尼（Francesco Bertoni）教授领导的淋巴瘤基因组学实验室（The Lymphoma Genomics Laboratory）确定了用于治疗滤泡性淋巴瘤（follicular lymphoma）、套细胞淋巴瘤（mantle cell lymphoma）和边缘区淋巴瘤（marginal zone lymphoma）患者的BTK和PI3K抑制剂耐药的新机制。相关报道详见“耐药性:发现了治疗B细胞淋巴瘤的一个新的关键机制”（Drug resistance: identified a new key mechanism in the treatment of B-cell lymphomas）

抗癌疗法治疗淋巴瘤失败的原因之一是耐药性的发展，这意味着某种药物的治疗效果下降。因此，研究这些耐药性背后的机制以优化药物在患者治疗中的使用是至关重要的。例如，依鲁替尼（ibrutinib）或泽布替尼（zanubrutinib）等靶向布鲁顿酪氨酸激酶(Bruton Tyrosine Kinase简称BTK)的药物，或艾代拉里斯（idelalisib）等靶向磷脂酰肌醇3激酶（phosphoinositide 3-kinase）的药物，已被美国食品和药物管理局(U.S. Food and Drug Administration简称FDA)和瑞士医学中心（SwissMedic）批准用于治疗各种淋巴瘤（lymphoma）或慢性淋巴细胞白血病（chronic lymphocytic leukemia）患者。虽然这些药物有效，但接触这些药物会产生耐药性，限制了它们的使用。

发现（The discovery）

在发表在《分子癌症治疗学》（Molecular Cancer Therapeutics）上的一项研究中，淋巴瘤基因组学研究小组（Lymphoma Genomics research group）发现了对BTK和PI3K抑制剂产生耐药性的新因素。详见Alberto J. Arribas; Sara Napoli; Luciano Cascione; Laura Barnabei; Giulio Sartori; Eleonora Cannas; Eugenio Gaudio; Chiara Tarantelli; Afua A. Mensah; Filippo Spriano; Antonella Zucchetto; Francesca M. Rossi; Andrea Rinaldi; Manuel Castro de Moura; Sandra Jovic; Roberta Bordone Pittau; Anastasios Stathis; Georg Stussi; Valter Gattei; Jennifer R. Brown; Manel Esteller; Emanuele Zucca; Davide Rossi; Francesco Bertoni. ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms. Molecular Cancer Therapeutics, 2023 Dec 5: OF1-OF13. DOI: 10.1158/1535-7163.MCT-23-0068. https://doi.org/10.1158/1535-7163.MCT-23-0068. bioRxiv [Preprint]. 2023 Jan 2:2023.01.01.522017. DOI: 10.1101/2023.01.01.522017. 

参与此项研究除了来自瑞士提契诺大学（USI, Bellinzona, Switzerland）的研究人员之外，还有来自瑞士生物信息学研究所（SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland）、瑞士南部肿瘤研究所（Oncology Institute of Southern Switzerland, Bellinzona, Switzerland）；意大利阿维亚诺肿瘤治疗中心（Centro di Riferimento Oncologico di Aviano – CRO, Aviano, Italy）、西班牙约瑟·卡雷拉斯白血病研究所{Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain}、西班牙癌症生物医学研究中心{Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain}、西班牙加泰罗尼亚高等教育研究所{Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain}、西班牙巴塞罗那大学（University of Barcelona, Barcelona, Catalonia, Spain）以及美国丹娜-法伯癌症研究所和哈佛医学院（Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA）的研究人员。

Alberto J. Arribas, Sara Napoli及其同事特别开发了一种细胞模型，模拟了在边缘区淋巴瘤患者中观察到的BTK和PI3K抑制剂耐药性。为此，他们将Karpas-1718淋巴瘤细胞系持续暴露于ideelalisib中，从而使细胞脱敏并产生耐药性。

对idelalisib耐药细胞的详细分析,使研究人员能够确定导致耐药的因素(ERBB4及其配体HBEGF和NRG2)以及如何解决它们。实验证实了该轴在阻断BTK/PI3K抑制剂抗肿瘤作用中的作用。通过对已确定的因子进行靶向治疗，研究人员能够克服耐药性，从而使细胞再次对BTK和PI3K抑制剂敏感。这些发现在临床标本中得到了证实，强调ERBB4过表达是对BTK和PI3K抑制剂的一种新的耐药机制，具有靶向干预恢复敏感性的潜力。

总之，由于Karpas-1718细胞中ideelalisib耐药的新模型，研究人员确定了导致耐药的因素，并证明针对这些因素的靶向治疗可以提高BTK和PI3K抑制剂的抗肿瘤活性。

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Abstract

BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead to long-lasting complete remission is rather limited, especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole-exome sequencing, and pharmacologic screening, which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the antitumor activity of various BTK/PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK/PI3K inhibitors in parental cells and in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. An epigenetic reprogramming sustained the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were also shown to be expressed in clinical specimens. In conclusion, we showed that the overexpression of ERBB4 and its ligands represents a novel mechanism of resistance for lymphoma cells to bypass the antitumor activity of BTK and PI3K inhibitors and that targeted pharmacologic interventions can restore sensitivity to the small molecules.