Egfr-Phosphorylated GDH1 Harmonizes With RSK2 to Drive Creb Activation and Tumor Metastasis in Egfr-Activated Lung Cancer

Authors

JiHoon Kang
Jaemoo Chun
Jung Seok Hwang
Chaoyun Pan
Jie Li
Austin C Boese
Isabelle Young
Courteney M Malin
Yibin Kang
Don L Gibbons
Gabriel Sica
Haian Fu
Suresh S Ramalingam
Lingtao Jin
Sumin Kang

Publication Date

12-13-2022

Journal

Cell Reports

Abstract

The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 leads to enhanced intratumoral CD8 T cell infiltration. Moreover, GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation and activation in lung cancer patient tumors. Our findings reveal a crosstalk between kinase, metabolic, and transcription machinery in metastasis and offer an alternative combinatorial therapeutic strategy to target metastatic cancers with activated EGFRs that are often EGFR therapy resistant.

Keywords

Humans, Cyclic AMP Response Element-Binding Protein, Ribosomal Protein S6 Kinases, 90-kDa, ErbB Receptors, Lung Neoplasms, Phosphorylation, Cell Line, Tumor, CP: Cancer, CREB, EGFR, EGFR mutations, GDH1, RSK2, cAMP response element-binding protein, epidermal growth factor receptor 1, glutamate dehydrogenase 1, metastasis, non-small cell lung carcinoma, oncogenic kinase signaling, ribosomal S6 kinase 2, tumor, tyrosine phosphorylation

DOI

10.1016/j.celrep.2022.111827

PMID

36516759

PMCID

PMC9813823

PubMedCentral® Posted Date

1-5-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes