The combined inhibition of SLC1A3 and glutaminase in osimertinib-resistant EGFR mutant cells

• Published in: Biochimica et biophysica acta. General subjects 2024-10, Vol.1868 (10), p.130675, Article 130675
• Main Authors: Ochi, Nobuaki, Miyake, Noriko, Takeyama, Masami, Yamane, Hiromichi, Fukazawa, Takuya, Nagasaki, Yasunari, Kawahara, Tatsuyuki, Ichiyama, Naruhiko, Kosaka, Youko, Mimura, Ayaka, Nakanishi, Hidekazu, Hiraki, Akio, Kiura, Katsuyuki, Takigawa, Nagio
• Format: Article
• Language: English
• Subjects: EGFR; Glutamic acid; Glutamine; Lung cancer; Metabolomics; SLC1A3
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130675

Background: We investigated the unknown mechanisms of osimertinib-resistant EGFR-mutant lung cancer. Methods: An osimertinib-resistant cell line (PC-9/OsmR2) was established through continuous exposure to osimertinib using an EGFR exon 19 deletion (19Del) lung adenocarcinoma cell line (PC-9). EGFR 19Del (M1), L858R/T790M/C797S (M6), and L858R/C797S (M8) expression vectors were introduced into Ba/F3 cells. A second osimertinib-resistant line (M1/OsmR) was established through continuous exposure to osimertinib using M1 cells. Results: SLC1A3 had the highest mRNA expression level in PC-9/OsmR2 compared to PC-9 cells by microarray analysis and SLC1A3 was increased by flow cytometry. In PC-9/OsmR2 cells, osimertinib sensitivity was significantly increased in combination with siSLC1A3. Because SLC1A3 functions in glutamic acid transport, osimertinib with a glutaminase inhibitor (CB-839) or an SLC1A3 inhibitor (TFB-TBOA) increased the sensitivity. Also, CB-839 plus TFB-TBOA without osimertinib resulted in greater susceptibility than did CB-839 or TFB-TBOA plus osimertinib. Comprehensive metabolome analysis showed that the M1/OsmR cells had significantly more glutamine and glutamic acid than M1 cells. CB-839 plus osimertinib exerted a synergistic effect on M6 cells and an additive effect on M8 cells. Conclusion: Targeting glutaminase and glutamic acid may overcome the osimertinib-resistant EGFR-mutant lung cancer. •SLC1A3 mRNA and protein were increased in an osimertinib-resistant cell line.•Osimertinib sensitivity was significantly increased in combination with siSLC1A3.•A glutaminase or an SLC1A3 inhibitor sensitized the resistant cells to osimertinib.•Osimertinib-resistant cells had significantly more glutamine than the parent cells.•Osimertinib with a glutaminase inhibitor was effective in EGFR C797S mutant cells.