@article{70c22e01b7cf4c499c0ccc8bd3162bf4,
title = "EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer",
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 = "cAMP response element-binding protein, CP: Cancer, CREB, EGFR, EGFR mutations, epidermal growth factor receptor 1, GDH1, glutamate dehydrogenase 1, metastasis, non-small cell lung carcinoma, oncogenic kinase signaling, ribosomal S6 kinase 2, RSK2, tumor, tyrosine phosphorylation",
author = "Kang, {Ji Hoon} and Jaemoo Chun and Hwang, {Jung Seok} and Chaoyun Pan and Jie Li and Boese, {Austin C.} and Isabelle Young and Malin, {Courteney M.} and Yibin Kang and Gibbons, {Don L.} and Gabriel Sica and Haian Fu and Ramalingam, {Suresh S.} and Lingtao Jin and Sumin Kang",
note = "Funding Information: We acknowledge Dr. Anthea Hammond for editorial assistance. This work was supported in part by NIH grants R01 CA175316 (S.K.), R01 CA207768 (S.K.), R01 CA266613 (S.K.), R37 CA249305 (L.J.), R01 CA269782 (L.J.), F99 CA264407 (A.C.B.), P50 CA217691 (S.R. and H.F), and P01 CA257906 (H.F. and S.R.); DoD W81XWH-21-1-0213 (S.K.); and the Integrated Cellular Imaging resource of Winship Cancer Institute of Emory University under NIH / NCI P30 CA138292 . A.C.B. is an NIH pre-doctoral fellow. S.K. is an American Cancer Society Basic Research Scholar and Georgia Cancer Coalition Scholar. Funding Information: We acknowledge Dr. Anthea Hammond for editorial assistance. This work was supported in part by NIH grants R01 CA175316 (S.K.), R01 CA207768 (S.K.), R01 CA266613 (S.K.), R37 CA249305 (L.J.), R01 CA269782 (L.J.), F99 CA264407 (A.C.B.), P50 CA217691 (S.R. and H.F), and P01 CA257906 (H.F. and S.R.); DoD W81XWH-21-1-0213 (S.K.); and the Integrated Cellular Imaging resource of Winship Cancer Institute of Emory University under NIH/NCI P30 CA138292. A.C.B. is an NIH pre-doctoral fellow. S.K. is an American Cancer Society Basic Research Scholar and Georgia Cancer Coalition Scholar. D.L.G. Y.K. H.F. and S.R. provided critical reagents. G.S. conducted histopathological analyses. I.Y. established metabolic inhibitor library. J.C. performed bioluminescence imaging and CaMKIV activity assay. L.J. conducted α-KG rescue experiment. C.P. and J.L. conducted part of the study related to EGFR-GDH1 link. J.K. J.S.H. A.C.B. and C.M.M. performed all other experiments. L.J. and S.K. designed the study, and J.K. and S.K. wrote the paper. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = dec,
day = "13",
doi = "10.1016/j.celrep.2022.111827",
language = "English (US)",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}