FGF2 Dual Warhead Conjugate with Monomethyl Auristatin E and α-Amanitin Displays a Cytotoxic Effect towards Cancer Cells Overproducing FGF Receptor 1

Świderska, K.; Szlachcic, Anna; Opaliński, Łukasz; Zakrzewska, Małgorzata; Otlewski, Jacek

doi:10.3390/ijms19072098

Cited by 25 publications

(29 citation statements)

References 37 publications

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“…Nevertheless, they usually contain a single cytotoxic drug, which can easily lead to the development of chemoresistance. Therefore, dual-drug conjugates, with two distinct mechanisms of action, showing enhanced efficacy and hindering the development of drug resistance, appear to be the future of anti-cancer strategies [ 268 , 269 ].…”

Section: Discussionmentioning

confidence: 99%

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Szymczyk

Sluzalska

Materla

et al. 2021

Cancers

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Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Szymczyk

Sluzalska

Materla

et al. 2021

Cancers

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“…Up to date, several ADCs have been approved and are commercially available for treatment of various cancers [18]. Importantly, a number of selective cytotoxic conjugates including ADCs against cancers overproducing FGFRs were generated,however, their in vivo therapeutic potential awaits further evaluation [20–27]. A critical step in the anti‐cancer therapy with ADCs is selective and efficient delivery of the cytotoxic drug to the cell interior [28].…”

Section: Introductionmentioning

confidence: 99%

FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization

et al. 2020

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Fibroblast growth factor receptor 1 (FGFR1) transmits signals through the plasma membrane regulating essential cellular processes like division, motility, metabolism, and death. Overexpression of FGFR1 is observed in numerous tumors and thus constitutes an attractive molecular target for selective cancer treatment. Targeted anti‐cancer therapies aim for the precise delivery of drugs into cancer cells, sparing the healthy ones and thus limiting unwanted side effects. One of the key steps in targeted drug delivery is receptor‐mediated endocytosis. Here, we show that the efficiency and the mechanism of FGFR1 internalization are governed by the spatial distribution of the receptor in the plasma membrane. Using engineered antibodies of different valency, we demonstrate that dimerization of FGFR1 with bivalent antibody triggers clathrin‐mediated endocytosis (CME) of the receptor. Clustering of FGFR1 into larger oligomers with tetravalent antibody stimulates fast and highly efficient uptake of the receptor that occurs via two distinct mechanisms: CME and dynamin‐dependent clathrin‐independent endocytic routes. Furthermore, we show that all endocytic pathways engaged in FGFR1 internalization do not require receptor activation. Our data provide novel insights into the mechanisms of intracellular trafficking of FGFR1 and constitute guidelines for development of highly internalizing antibody‐based drug carriers for targeted therapy of FGFR1‐overproducing cancers.

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“…Loci for conjugation on the toxin include the δhydroxyl of dihydroxyisoleucine, 27,48 the asparagine side chain, 49 and the 6'-hydroxyl of the tryptathionine staple. 28,29,31,50,51 In some cases, these have been linked either to reducible or proteolyzable linkers, or to linkers assumed to be non-cleavable for which the metabolic fate is usually unknown. A key advance in the development of any cytotoxic payload is access to synthetic toxins and analogs thereof.…”

Section: Resultsmentioning

confidence: 99%