Pharmacologically targeting the myristoylation of the scaffold protein FRS2 inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression

Qianjin Li, Omar Awad Alsaidan, Yongjie Ma, Sungjin Kim, Junchen Liu, Thomas Albers, Kebin Liu, Zanna Beharry, Shaying Zhao, Fen Wang, Iryna Lebedyeva, Houjian Cai

Research output: Contribution to journalArticle

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Abstract

Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling facilitates tumor initiation and progression. Although currently approved inhibitors of FGFR kinase have shown therapeutic benefit in clinical trials, overexpression or mutations of FGFRs eventually confer drug resistance and thereby abrogate the desired activity of kinase inhibitors in many cancer types. In this study, we report that loss of myristoylation of fibroblast growth factor receptor substrate 2 (FRS2), a scaffold protein essential for FGFR signaling, inhibits FGF/FGFR-mediated oncogenic signaling and FGF10-induced tumorigenesis. Moreover, a previously synthesized myristoyl-CoA analog, B13, which targets the activity of N-myristoyltransferases, suppressed FRS2 myristoylation and decreased the phosphorylation with mild alteration of FRS2 localization at the cell membrane. B13 inhibited oncogenic signaling induced by WT FGFRs or their drug-resistant mutants (FGFRsDRM). B13 alone or in combination with an FGFR inhibitor suppressed FGF-induced WT FGFR- or FGFRDRM-initiated phosphoinositide 3-kinase (PI3K) activity or MAPK signaling, inducing cell cycle arrest and thereby inhibiting cell proliferation and migration in several cancer cell types. Finally, B13 significantly inhibited the growth of xenograft tumors without pathological toxicity to the liver, kidney, or lung in vivo. In summary, our study suggests a possible therapeutic approach for inhibiting FGF/FGFR-mediated cancer progression and drug-resistant FGF/FGFR mutants.

Original languageEnglish (US)
Pages (from-to)6434-6448
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number17
DOIs
StatePublished - Jan 1 2018

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Fibroblast Growth Factor Receptors
Fibroblast Growth Factors
Fibroblast Growth Factor 2
Scaffolds
Tumors
Substrates
Neoplasms
Proteins
Phosphotransferases
Receptor, Fibroblast Growth Factor, Type 2
Pharmaceutical Preparations
Cell signaling
1-Phosphatidylinositol 4-Kinase
Phosphorylation
Cell Cycle Checkpoints
Drug Resistance
Heterografts
Cell proliferation
Cell membranes
Phosphatidylinositols

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Pharmacologically targeting the myristoylation of the scaffold protein FRS2 inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. / Li, Qianjin; Alsaidan, Omar Awad; Ma, Yongjie; Kim, Sungjin; Liu, Junchen; Albers, Thomas; Liu, Kebin; Beharry, Zanna; Zhao, Shaying; Wang, Fen; Lebedyeva, Iryna; Cai, Houjian.

In: Journal of Biological Chemistry, Vol. 293, No. 17, 01.01.2018, p. 6434-6448.

Research output: Contribution to journalArticle

Li, Qianjin ; Alsaidan, Omar Awad ; Ma, Yongjie ; Kim, Sungjin ; Liu, Junchen ; Albers, Thomas ; Liu, Kebin ; Beharry, Zanna ; Zhao, Shaying ; Wang, Fen ; Lebedyeva, Iryna ; Cai, Houjian. / Pharmacologically targeting the myristoylation of the scaffold protein FRS2 inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 17. pp. 6434-6448.
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abstract = "Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling facilitates tumor initiation and progression. Although currently approved inhibitors of FGFR kinase have shown therapeutic benefit in clinical trials, overexpression or mutations of FGFRs eventually confer drug resistance and thereby abrogate the desired activity of kinase inhibitors in many cancer types. In this study, we report that loss of myristoylation of fibroblast growth factor receptor substrate 2 (FRS2), a scaffold protein essential for FGFR signaling, inhibits FGF/FGFR-mediated oncogenic signaling and FGF10-induced tumorigenesis. Moreover, a previously synthesized myristoyl-CoA analog, B13, which targets the activity of N-myristoyltransferases, suppressed FRS2 myristoylation and decreased the phosphorylation with mild alteration of FRS2 localization at the cell membrane. B13 inhibited oncogenic signaling induced by WT FGFRs or their drug-resistant mutants (FGFRsDRM). B13 alone or in combination with an FGFR inhibitor suppressed FGF-induced WT FGFR- or FGFRDRM-initiated phosphoinositide 3-kinase (PI3K) activity or MAPK signaling, inducing cell cycle arrest and thereby inhibiting cell proliferation and migration in several cancer cell types. Finally, B13 significantly inhibited the growth of xenograft tumors without pathological toxicity to the liver, kidney, or lung in vivo. In summary, our study suggests a possible therapeutic approach for inhibiting FGF/FGFR-mediated cancer progression and drug-resistant FGF/FGFR mutants.",
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AU - Kim, Sungjin

AU - Liu, Junchen

AU - Albers, Thomas

AU - Liu, Kebin

AU - Beharry, Zanna

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AU - Lebedyeva, Iryna

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