2. Academic Validation
  3. EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer

EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer

  • Cell Rep. 2022 Dec 13;41(11):111827. doi: 10.1016/j.celrep.2022.111827.
JiHoon Kang 1,  Jaemoo Chun 1,  Jung Seok Hwang 1,  Chaoyun Pan 1,  Jie Li 1,  Austin C Boese 1,  Isabelle Young 1,  Courteney M Malin 1,  Yibin Kang 2,  Don L Gibbons 3,  Gabriel Sica 4,  Haian Fu 5,  Suresh S Ramalingam 1,  Lingtao Jin 6,  Sumin Kang 7
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2 Department of Molecular Biology, Princeton University, and Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ 08544, USA.
  • 3 Department of Thoracic-Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 5 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 6 Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX 78229, USA. Electronic address: jinl1@uthscsa.edu.
  • 7 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: smkang@emory.edu.
PMID: 36516759 DOI: 10.1016/j.celrep.2022.111827
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

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.

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