Abstract 7032: GLAST (SLC1A3), a novel therapeutic target for overcoming osimertinib resistance in lung cancer.

Abstract Lung cancer is the leading cause of cancer-related death in the U.S. with EGFR-mutant non-small cell lung cancer (NSCLC) as the second most common subtype. Although osimertinib, a third-generation EGFR inhibitor, is the preferred first-line treatment and significantly improves outcomes, resistance inevitably develops. The mechanisms driving this resistance are not fully understood, with current research primarily focused on genetic alterations while non-genetic, metabolic factors remain largely unexplored. This knowledge gap limits our ability to design effective therapies to overcome resistance. The objective of this study is to investigate the metabolic pathways that EGFR-mutant NSCLC cells exploit to develop osimertinib resistance. Prior studies with earlier EGFR inhibitors suggest that cancer cells rewire glutamine metabolism to survive EGFR inhibition; therefore we hypothesize that upregulation of glutamine metabolism enables lung cancer cells to acquire osimertinib resistance. To test this hypothesis, osimertinib-resistant and -naive NSCLC cell lines were established from xenograft tumors in mice, and levels of enzymes and transporters in glutamine metabolism were compared. Osimertinib-resistant cells exhibited increased expression of GLAST (SLC1A3), a glutamate transporter, compared to naive cells. Both genetic and pharmacological inhibition of GLAST selectively reduced viability of osimertinib-resistant but not -naive cells. Additionally, patient whole exome sequencing data showed that high GLAST expression correlates with poor prognosis in osimertinib-treated patients.These findings identify GLAST as a novel therapeutic target to overcome osimertinib resistance in EGFR-mutant NSCLC. Citation Format: Sara Bernstein, Sophie Kim, Clara Takanohashi, Beatriz P. Peixoto, Kathy Nguyen, Hiromi Inoue Wettersten. GLAST (SLC1A3), a novel therapeutic target for overcoming osimertinib resistance in lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7032.