Abstract 2409: EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR mutated cancers

Abstract

Abstract Cancer metastasis process involves dysregulated oncogenic kinase signaling, but the precise mechanism by which this orchestrates metabolic networks and signal cascades for metastasis is largely unclear. Here we report that pharmacological inhibition of a glutaminolytic enzyme glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape more evidently in tumors harboring EGFR activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135, and together with RSK2 enhances transcriptional activity of CREB via CaMKIV signaling fostering metastasis. Moreover, GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation status and metastatic cancer progression in primary patient tumors. Our finding reveals a crosstalk between kinase, metabolic, and transcription machinery in metastasis and offers an alternative combinatorial therapeutic strategy to target EGFR therapy-resistant metastatic cancers. Citation Format: JiHoon Kang, Jung Seok Hwang, Austin Boese, Courteney Malin, Sumin Kang. EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2409.