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Published on: August 11, 2017
Anthrax toxin receptor 2 is a potential therapeutic target for non-small cell lung carcinoma with MET exon 14
Miki Yamaguchi1, Sachie Hirai1, Masashi Idogawa2
1Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Abstract:
Although MET tyrosine kinase inhibitors (TKIs) are generally effective against non-small cell lung carcinoma (NSCLC) with MET exon 14 skipping mutations (METΔex14), resistance to MET TKIs can occur, indicating the need to develop other therapeutic options. We found that Hs-746 T cells, which harbor METΔex14 plus amplification, were able to survive and grow in the absence of MET signaling, exhibiting primary resistance to MET TKIs. We also found a moderately positive correlation between MET and anthrax toxin receptor 2 (ANTXR2) mRNA expression in NSCLC cell lines using data from the Cancer Dependency Map database. As expected, Hs-746 T cells were positive for ANTXR2 expression. We used an antibody-drug conjugate (ADC) analog in the form of an anti-ANTXR2 monoclonal antibody, H8R23, conjugated to DT3C recombinant protein which consists of diphtheria toxin (DT) lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G (3C). H8R23-DT3C conjugates, which function in vitro like an ADC, induced Hs-746 T cells to undergo apoptosis, resulting in decreased viability. These findings collectively suggest that an ADC targeting ANTXR2 could be effective for the treatment of METΔex14-positive NSCLC.
Insights
MET tyrosine kinase inhibitors (TKIs) are less effective for some non-small cell lung cancers (NSCLC). Targeting anthrax toxin receptor 2 (ANTXR2) with an antibody-drug conjugate (ADC) shows promise for treating resistant MET-altered NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- MET tyrosine kinase inhibitors (TKIs) are standard treatments for non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations (METΔex14).
- Primary resistance to MET TKIs can occur in NSCLC, necessitating alternative therapeutic strategies.
- Anthrax toxin receptor 2 (ANTXR2) expression is correlated with MET expression in NSCLC cell lines.
Purpose of the Study:
- To investigate alternative therapeutic targets for MET-altered NSCLC exhibiting primary resistance to MET TKIs.
- To evaluate the efficacy of an antibody-drug conjugate (ADC) targeting ANTXR2 in resistant NSCLC cells.
Main Methods:
- Utilized Hs-746T cells, a METΔex14-positive NSCLC cell line with amplification and primary resistance to MET TKIs.
- Analyzed correlation between MET and ANTXR2 mRNA expression in NSCLC cell lines using Cancer Dependency Map data.
- Developed and tested an anti-ANTXR2 monoclonal antibody (H8R23) conjugated to a diphtheria toxin fragment (DT3C) as an ADC analog.
Main Results:
- Hs-746T cells demonstrated survival and growth despite MET signaling absence, indicating primary resistance to MET TKIs.
- A positive correlation was observed between MET and ANTXR2 mRNA expression in NSCLC cell lines.
- The H8R23-DT3C conjugate induced apoptosis and reduced viability in Hs-746T cells in vitro.
Conclusions:
- ANTXR2 is a potential therapeutic target in MET-altered NSCLC.
- An antibody-drug conjugate (ADC) targeting ANTXR2 is a promising strategy for treating METΔex14-positive NSCLC, particularly cases resistant to MET TKIs.
