Abstract
In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: α-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug-FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead-FGF2 conjugate may overcome the potential acquired resistance of FGFR1-overproducing cancer cells towards single cytotoxic drugs.
Highlights
Fibroblast growth factor receptors (FGFR) comprise a group of four cell surface proteins that upon activation by fibroblast growth factors (FGFs) transmit signals from an extracellular environment, leading to cell proliferation, cell motility and the inhibition of apoptosis [1]
We have recently demonstrated that fibroblast growth factor 2 (FGF2), a natural ligand of fibroblast growth factor receptors (FGFRs), can be used as an alternative to antibodies for the selective and efficient delivery of cytotoxic drugs into cancer cells overproducing FGFRs [13]
FGF2-based dual warhead conjugate kills cancer cells more efficiently than single drug conjugates, and has the potential to limit the ability of cancer cells to develop resistance to cytotoxic drugs, which is a well-known feature of various cancers [17,18]
Summary
Fibroblast growth factor receptors (FGFR) comprise a group of four cell surface proteins that upon activation by fibroblast growth factors (FGFs) transmit signals from an extracellular environment, leading to cell proliferation, cell motility and the inhibition of apoptosis [1]. Antibody Drug Conjugates (ADCs), which combine therapeutic potency of small cytotoxic molecules and targeting properties of antibodies binding malignant cells, are important players in the field of targeted anti-cancer therapy [6,7]. The FGF2 dual warhead conjugate is designed to allow for site-specific conjugation of each cytotoxic compound via two different conjugation strategies: Thiol-maleimide reaction and Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC). We describe the development of a site-specific FGF2 dual warhead conjugate combining α-amanitin and MMAE by using thiol-maleimide and Cu(I)-catalyzed alkyne-azide cycloaddition, respectively. Our results on FGFR1-positive cancer cell lines show that the conjugate is efficiently targeting cells expressing FGFR1, leading to excellent and selective toxicity due to the combined cytotoxic effect of MMAE and α-amanitin. FGF2-based dual warhead conjugate kills cancer cells more efficiently than single drug conjugates, and has the potential to limit the ability of cancer cells to develop resistance to cytotoxic drugs, which is a well-known feature of various cancers [17,18]
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