A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R. (7th April 2021)

• Record Type: Journal Article
• Authors: Makimoto, Go; Ninomiya, Kiichiro; Kubo, Toshio; Sunami, Ryota; Kato, Yuka; Ichihara, Eiki; Ohashi, Kadoaki; Rai, Kammei; Hotta, Katsuyuki; Tabata, Masahiro; Maeda, Yoshinobu; Kiura, Katsuyuki
• Is Part Of: Japanese journal of clinical oncology. Volume 51:Number 6(2021)
• Page Start: 956
• Page End: 965
• Publication Date: 2021-04-07
• Subjects: EGFR -- osimertinib -- resistance -- IGF1R -- re-administration; Oncology -- Periodicals; Cancer -- Periodicals; 616.994005
• DOI: 10.1093/jjco/hyab048
• Languages: English
• ISSNs: 0368-2811

Abstract

Abstract: 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. Abstract : This study describes the successful establishment of the novel ABC-31 cell line from a 63-year-old Japanese patient with lung adenocarcinoma.