Affibody-conjugated 5-fluorouracil prodrug system preferentially targets and inhibits HER2-expressing cancer cells

Keng Hsueh Lan, Cheng Liang Tsai, Yu Yi Chen, Tun Ling Lee, Chiung Wen Pai, Yee Chao, Keng Li Lan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Overexpression of HER2 is associated with cancer phenotypes, such as proliferation, survival, metastasis and angiogenesis, and has been validated as a therapeutic target. However, only a portion of patients benefited from anti-HER2 treatments, and many would develop resistance. A more effective HER2 targeted therapeutics is needed. Here, we adopted a prodrug system that uses 5-fluorocytosine (5-FC) and a HER2-targeting scaffold protein, ZHER2:2891, fused with yeast cytosine deaminase (Fcy) to target HER2-overexpressing cancer cells and to convert 5-FC to a significantly more toxic chemotherapeutic, 5-fluorouracil (5-FU). We cloned the coding gene of ZHER2:2891 and fused with those of ABD (albumin-binding domain) and Fcy. The purified ZHER2:2891-ABD-Fcy fusion protein specifically binds to HER2 with a Kd value of 1.6 nM ZHER2:2891-ABD-Fcy binds to MDA-MB-468, SKOV-3, BT474, and MC38-HER2 cells, which overexpress HER2, whereas with a lower affinity to HER2 non-expresser, MC38. Correspondingly, the viability of HER2-expressing cells was suppressed by relative low concentrations of ZHER2:2891-ABD-Fcy in the presence of 5-FC, and the IC50 values of ZHER2:2891-ABD-Fcy for HER2 high-expresser cells were approximately 10–1000 fold lower than those of non-HER2-targeting Fcy, and ABD-Fcy. This novel prodrug system, ZHER2:2891-ABD-Fcy/5-FC, might become a promising addition to the existing class of therapeutics specifically target HER2-expressing cancers.

Original languageEnglish
Pages (from-to)137-143
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume582
DOIs
StatePublished - 10 Dec 2021

Keywords

  • 5-fluorocytosine (5-FC)
  • 5-fluorouracil (5-FU)
  • Cytosine deaminase
  • HER2
  • Prodrug
  • ZHER2:2891 affibody

Fingerprint

Dive into the research topics of 'Affibody-conjugated 5-fluorouracil prodrug system preferentially targets and inhibits HER2-expressing cancer cells'. Together they form a unique fingerprint.

Cite this