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. 2024 Oct;1868(10):130675.
doi: 10.1016/j.bbagen.2024.130675. Epub 2024 Jul 24.

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

Nobuaki Ochi  1 , Noriko Miyake  2 , Masami Takeyama  1 , Hiromichi Yamane  1 , Takuya Fukazawa  3 , Yasunari Nagasaki  1 , Tatsuyuki Kawahara  1 , Naruhiko Ichiyama  1 , Youko Kosaka  1 , Ayaka Mimura  1 , Hidekazu Nakanishi  1 , Akio Hiraki  4 , Katsuyuki Kiura  4 , Nagio Takigawa  5
Affiliations

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

Nobuaki Ochi et al. Biochim Biophys Acta Gen Subj. 2024 Oct.

Abstract

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.

Keywords: EGFR; Glutamic acid; Glutamine; Lung cancer; Metabolomics; SLC1A3.

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Conflict of interest statement

Declaration of competing interest Dr. Takigawa has received grants and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer-Ingelheim Japan, and Ono Pharmaceutical; grants from Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; and personal fees from MSD and Bristol-Myers Squibb Company Japan outside the submitted work. Dr. Ochi has received personal fees from Eli Lilly Japan K.K., Taiho Pharmaceutical Co. ltd., Chugai Pharmaceutical, Pfizer Japan Inc., Ono pharmaceutical, MSD, Bristol-Myers Squibb, Boehringer Ingelheim, and Nippon Kayaku outside the submitted work. Dr. Fukazawa has received personal fees from Boehringer-Ingelheim Japan outside the submitted work. Dr. Kiura has received grants and personal fees from Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical, Chugai Pharmaceutical, Nippon Kayaku Co., Ltd., Teijin Pharma Ltd., Shionogi Pharma Co., Ltd., Novartis Pharma, Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., MSD, and Pfizer Japan Inc. and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Bristol-Myers Squibb, and Nipro Pharma Co. outside the submitted work. The other authors have no conflicts of interest to declare.

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