Targeting EGFR-dependent Tumors by Disrupting an ARF6-mediated Sorting System

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 12

PMID 36224181

Authors

Huiling Guo

Juan Wang

Su Ren

Lang-Fan Zheng

Yi-Xuan Zhuang

Dong-Lin Li

Hui-Hui Sun

Li-Ying Liu

Changchuan Xie

Ya-Ying Wu

Hong-Rui Wang

Xianming Deng

Peng Li

Tong-Jin Zhao

Affiliations

Soon will be listed here.

Abstract

Aberrant activation of EGFR due to overexpression or mutation is associated with poor prognosis in many types of tumors. Here we show that blocking the sorting system that directs EGFR to plasma membrane is a potent strategy to treat EGFR-dependent tumors. We find that EGFR palmitoylation by DHHC13 is critical for its plasma membrane localization and identify ARF6 as a key factor in this process. N-myristoylated ARF6 recognizes palmitoylated EGFR via lipid-lipid interaction, recruits the exocyst complex to promote EGFR budding from Golgi, and facilitates EGFR transporting to plasma membrane in a GTP-bound form. To evaluate the therapeutic potential of this sorting system, we design a cell-permeable peptide, N-myristoylated GKVL-TAT, and find it effectively disrupts plasma membrane localization of EGFR and significantly inhibits progression of EGFR-dependent tumors. Our findings shed lights on the underlying mechanism of how palmitoylation directs protein sorting and provide an potential strategy to manage EGFR-dependent tumors.

Citing Articles

zDHHC-Mediated S-Palmitoylation in Skin Health and Its Targeting as a Treatment Perspective.

Abdulrahman F, Benford K, Lin G, Maroun A, Sammons C, Shirzad D Int J Mol Sci. 2025; 26(4).

PMID: 40004137 PMC: 11854935. DOI: 10.3390/ijms26041673.

Recapitulating the potential contribution of protein S-palmitoylation in cancer.

Chaturvedi S, Sonawane A Cancer Metastasis Rev. 2024; 44(1):20.

PMID: 39725785 DOI: 10.1007/s10555-024-10217-3.

Discovery of a molecular glue for EGFR degradation.

Wang H, Wang H, Wang R, Li Y, Wang Z, Zhou W Oncogene. 2024; 44(8):545-556.

PMID: 39627505 DOI: 10.1038/s41388-024-03241-8.

A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas.

Sangha R, Jamal R, Spratlin J, Kuruvilla J, Sehn L, Beauchamp E Invest New Drugs. 2024; 42(4):386-393.

PMID: 38837078 PMC: 11327210. DOI: 10.1007/s10637-024-01448-w.

Membrane trafficking alterations in breast cancer progression.

Ferreira A, Castanheira P, Escrevente C, Barral D, Barona T Front Cell Dev Biol. 2024; 12:1350097.

PMID: 38533085 PMC: 10963426. DOI: 10.3389/fcell.2024.1350097.

References

El Guerrab A, Bamdad M, Kwiatkowski F, Bignon Y, Penault-Llorca F, Aubel C . Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer. Oncotarget. 2016; 7(45):73618-73637. PMC: 5342003. DOI: 10.18632/oncotarget.12037. View

Seshacharyulu P, Ponnusamy M, Haridas D, Jain M, Ganti A, Batra S . Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012; 16(1):15-31. PMC: 3291787. DOI: 10.1517/14728222.2011.648617. View

Roskoski Jr R . The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2013; 79:34-74. DOI: 10.1016/j.phrs.2013.11.002. View

Tsuchiya M, Price S, Tsai S, Moss J, Vaughan M . Molecular identification of ADP-ribosylation factor mRNAs and their expression in mammalian cells. J Biol Chem. 1991; 266(5):2772-7. View

Boncompain G, Divoux S, Gareil N, de Forges H, Lescure A, Latreche L . Synchronization of secretory protein traffic in populations of cells. Nat Methods. 2012; 9(5):493-8. DOI: 10.1038/nmeth.1928. View

Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gustafsdottir S . Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol. 2002; 20(5):473-7. DOI: 10.1038/nbt0502-473. View

Antonny B, Chardin P, Chabre M . N-terminal hydrophobic residues of the G-protein ADP-ribosylation factor-1 insert into membrane phospholipids upon GDP to GTP exchange. Biochemistry. 1997; 36(15):4675-84. DOI: 10.1021/bi962252b. View

Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson B, Janne P . Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res. 2004; 64(20):7241-4. DOI: 10.1158/0008-5472.CAN-04-1905. View

Stenmark H . Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009; 10(8):513-25. DOI: 10.1038/nrm2728. View

10.

Mitchell D, Vasudevan A, Linder M, Deschenes R . Protein palmitoylation by a family of DHHC protein S-acyltransferases. J Lipid Res. 2006; 47(6):1118-27. DOI: 10.1194/jlr.R600007-JLR200. View

11.

Morishige M, Hashimoto S, Ogawa E, Toda Y, Kotani H, Hirose M . GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion. Nat Cell Biol. 2007; 10(1):85-92. DOI: 10.1038/ncb1672. View

12.

Runkle K, Kharbanda A, Stypulkowski E, Cao X, Wang W, Garcia B . Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling. Mol Cell. 2016; 62(3):385-396. PMC: 4860254. DOI: 10.1016/j.molcel.2016.04.003. View

13.

Mitsudomi T, Yatabe Y . Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 2007; 98(12):1817-24. PMC: 11159145. DOI: 10.1111/j.1349-7006.2007.00607.x. View

14.

Greaves J, Chamberlain L . Palmitoylation-dependent protein sorting. J Cell Biol. 2007; 176(3):249-54. PMC: 2063950. DOI: 10.1083/jcb.200610151. View

15.

Xu M, Johnson D, Grandis J . EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev. 2017; 36(3):463-473. PMC: 5693744. DOI: 10.1007/s10555-017-9687-8. View

16.

Wu B, Guo W . The Exocyst at a Glance. J Cell Sci. 2015; 128(16):2957-64. PMC: 4541039. DOI: 10.1242/jcs.156398. View

17.

Chabu C, Li D, Xu T . EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth. Nat Commun. 2017; 8:14688. PMC: 5353614. DOI: 10.1038/ncomms14688. View

18.

Simek M, Rida W, Priddy F, Pung P, Carrow E, Laufer D . Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J Virol. 2009; 83(14):7337-48. PMC: 2704778. DOI: 10.1128/JVI.00110-09. View

19.

Hongu T, Kanaho Y . Activation machinery of the small GTPase Arf6. Adv Biol Regul. 2013; 54:59-66. DOI: 10.1016/j.jbior.2013.09.014. View

20.

Nakai K, Hung M, Yamaguchi H . A perspective on anti-EGFR therapies targeting triple-negative breast cancer. Am J Cancer Res. 2016; 6(8):1609-23. PMC: 5004067. View