A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R
A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R
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DOI：
10.1093/jjco/hyab048
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发表时间：
2021-04-08
影响因子：
2.4
通讯作者：
Kiura, Katsuyuki
中科院分区：
文献类型：
--
作者：
Makimoto, Go;Ninomiya, Kiichiro;Kiura, Katsuyuki
目的：第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）奥希替尼是携带突变型EGFR的非小细胞肺癌患者的标准治疗药物。不幸的是，这些患者不可避免地获得对EGFR-TKI疗法的抗性，包括奥希替尼。然而，与这种阻力的机制仍不清楚。方法：一个63岁的日本女性肺腺癌进行右上叶切除术（pT 1bN 2 M0 pStage IIIA，EGFR Ex 21 L 858 R）。8个月后，患者出现术后肿瘤复发伴多发性肺转移，并开始吉非替尼治疗。15个月后肺部病灶复发，肺转移再活检中检测到EGFR T790 M突变。她接受了奥希替尼治疗;然而，16个月后复发伴胸腔积液。我们从奥西替尼耐药的胸腔积液中分离细胞，建立了一种新的细胞系ABC-31。结果：ABC-31细胞中虽然检测到EGFR L 858 R突变，但T790 M突变丢失。ABC-31细胞对EGFR-TKI耐药，包括奥希替尼。磷酸化受体酪氨酸激酶阵列显示胰岛素样生长因子1受体（IGF 1 R）的激活，而IGF 1 R配体IGF 2的过表达诱导ABC-31细胞中IGF 1 R的激活。使用EGFR-TKI和IGF 1 R抑制剂的联合治疗在体外协同作用。由于EGFR-TKI和IGF 1 R抑制剂联合治疗在临床实践中是不可能的，因此她重新接受了奥希替尼给药。这有一个轻微的和短暂的effects.Conclusions：综上所述，我们已经成功地建立了一个新的奥斯替尼耐药肺腺癌细胞系与激活IGF 1 R。这些ABC-31细胞将有助于开发新的治疗策略，用于对通过IGF 1 R激活的特异性治疗耐药的肺腺癌患者。
Objective: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear.Methods: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31.Results: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect.Conclusions: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.