Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression.

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 (FRS2α), 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 FRS2α myristoylation and decreased the phosphorylation with mild alteration of FRS2α 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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 17 Pg. 6434-6448 (04 27 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29540482 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Amides
• FRS2 protein, human
• FRS2alpha protein, mouse
• Membrane Proteins
• N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide
• Neoplasm Proteins
• Propanolamines
• Receptors, Fibroblast Growth Factor
• Fibroblast Growth Factors
• Phosphatidylinositol 3-Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Amides (pharmacology)
• Animals
• Cell Line, Tumor
• Fibroblast Growth Factors (genetics, metabolism)
• Humans
• Lipoylation (drug effects)
• MAP Kinase Signaling System (drug effects)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, SCID
• NIH 3T3 Cells
• Neoplasm Proteins (drug effects, genetics, metabolism)
• Neoplasms, Experimental (drug therapy, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Propanolamines (pharmacology)
• Prostatic Neoplasms (genetics, metabolism)
• Receptors, Fibroblast Growth Factor (genetics, metabolism)