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.

中文翻译：

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ERBB4 介导的信号传导是 B 细胞淋巴肿瘤中 PI3K 和 BTK 抑制剂耐药性的介质

BTK 和 PI3K 抑制剂是批准用于治疗淋巴肿瘤患者的药物。尽管很活跃，但它们导致持久完全缓解的能力相当有限，特别是在淋巴瘤环境中。这表明肿瘤细胞经常对药物产生耐药性。我们从边缘区淋巴瘤细胞系 Karpas-1718 开始，长期暴露于 PI3Kδ 抑制剂 idelalisib，直到获得耐药性或不使用药物。对细胞进行转录组、miRNA 和甲基化分析、全外显子组测序和药理学筛选，从而鉴定出耐药细胞中 ERBB4 及其配体 HBEGF 和 NRG2 的过度表达。细胞和遗传实验证明该轴参与阻断目前临床使用的各种 BTK/PI3K 抑制剂的抗肿瘤活性。添加重组 HBEGF 可诱导亲代细胞和其他淋巴瘤模型对 BTK/PI3K 抑制剂产生耐药性。与 ERBB 抑制剂拉帕替尼联合治疗对耐药细胞和其他已经表达已识别耐药因子的淋巴瘤模型有益。表观遗传重编程维持了耐药相关因子的表达，并且用去甲基化剂或 EZH2 抑制剂进行预处理克服了耐药性。临床标本中也显示出耐药因素。总之，我们表明，ERBB4 及其配体的过度表达代表了淋巴瘤细胞绕过 BTK 和 PI3K 抑制剂的抗肿瘤活性的新耐药机制，并且靶向药物干预可以恢复对小分子的敏感性。