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Published on: January 7, 2019
Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant
Swati Choudhary1, Alessa Pardo2, Reinhard Rosinke3
1Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India.
Abstract:
Autocrine activation of c-kit (KIT receptor tyrosine kinase) has been postulated to be a potent oncogenic driver in small cell lung cancer, neuroblastoma (NB), and poorly differentiated colorectal carcinoma (CRC). Although targeted therapy involving tyrosine kinase inhibitors (TKIs) such as imatinib mesylate is highly effective for gastrointestinal stromal tumor carrying V560G c-kit mutation, it does not show much potential for targeting wild-type KIT (WT-KIT). Our study demonstrates the role of stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing malignancies such as NBs and CRCs. We constructed SCF-based recombinant bacterial toxins by genetically fusing mutated form of natural ligand SCF to receptor binding deficient forms of Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA') and evaluated their efficacy in vitro. Efficient targeting was achieved in all receptor-positive neuroblastoma (IMR-32 and SHSY5Y) and colon cancer cell lines (COLO 320DM, HCT 116, and DLD-1) but not in receptor-negative breast carcinoma cell line (MCF-7) thereby proving specificity. While dose- and time-dependent cytotoxicity was observed in both neuroblastoma cell lines, COLO 320DM and HCT 116 cells, only an anti-proliferative effect was observed in DLD-1 cells. We prove that these novel targeting agents have promising potential as KIT receptor tyrosine kinase targeting system.
Insights
This study developed novel stem cell factor (SCF)-based toxin conjugates to target wild-type KIT (WT-KIT) in cancers like neuroblastoma and colorectal cancer. These agents show promising potential for treating WT-KIT-overexpressing malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Autocrine c-kit (KIT receptor tyrosine kinase) activation drives cancers like neuroblastoma and colorectal cancer.
- Tyrosine kinase inhibitors are effective for KIT mutations but not wild-type KIT (WT-KIT).
- Targeting WT-KIT-overexpressing malignancies remains a challenge.
Purpose of the Study:
- To develop and evaluate novel stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing cancers.
- To assess the specificity and efficacy of these conjugates against neuroblastoma and colorectal cancer cell lines.
Main Methods:
- Constructed recombinant bacterial toxins by fusing SCF ligand to Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA').
- Evaluated the efficacy of SCF-based toxin conjugates in vitro using receptor-positive and negative cancer cell lines.
- Assessed dose- and time-dependent cytotoxicity and anti-proliferative effects.
Main Results:
- SCF-based toxin conjugates demonstrated efficient and specific targeting of WT-KIT-expressing neuroblastoma and colorectal cancer cells.
- Significant dose- and time-dependent cytotoxicity was observed in neuroblastoma and some colorectal cancer cell lines.
- An anti-proliferative effect was noted in other colorectal cancer cell lines, indicating varying responses.
Conclusions:
- Novel SCF-based toxin conjugates are effective in targeting WT-KIT-overexpressing malignancies.
- These agents show promise as a new therapeutic strategy for neuroblastoma and colorectal cancer.
- Further research is warranted to optimize these conjugates for clinical application.
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