Lysosomal P-gp-MDR1 Confers Drug Resistance of Brentuximab Vedotin and Its Cytotoxic Payload Monomethyl Auristatin E in Tumor Cells

Frontiers in Pharmacology
Peggy Liu-KreycheYurong Lai

Abstract

Antibody-drug conjugates (ADCs) are composed of an antibody linked to cytotoxic anticancer payloads. ADCs recognize tumor-specific cell surface antigens and are internalized into lysosomes where proteolytic enzymes release the cytotoxic payloads. Efflux transporters on plasma membrane that play a significant role on multi-drug resistance in chemotherapy can be internalized on lysosomal membrane and sequester the cytotoxic payloads. In the present study, ATP binding cassette (ABC) efflux transporters including breast cancer resistance protein (BCRP), P-glycoprotein (P-gp-MDR1), multidrug resistance protein (MRP) 2, MRP3 and MRP4 in lysosomal, and plasma membrane of tumor cells were quantified by targeted quantitative proteomics. The cytotoxicity of brentuximab vedotin and its cytotoxic payload monomethyl auristatin E (MMAE) to the tumor cell lines in the presence and absence of elacridar (P-gp-MDR1 inhibitor) or chloroquine (lysosomotropic agent) were evaluated. MMAE is a substrate for P-gp-MDR1, as the apparent efflux ratio in MDR1 transfected MDCK cell monolayers was 44.5, and elacridar abolished the MMAE efflux. Cell lines that highly express P-gp-MDR1 show higher EC50s toward the cell killing effects of MMAE. Co-incubation w...Continue Reading

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Citations

Sep 15, 2020·Technology in Cancer Research & Treatment·Ting ZhanXiaodong Huang
Jul 9, 2020·Frontiers in Immunology·Wassilis S C BruinsNiels W C J van de Donk
Oct 25, 2020·FEBS Letters·Gergely Szakacs, Rupert Abele
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Dec 5, 2020·Molecular Cancer Therapeutics·Ryan D LyskiScott C Jeffrey
Dec 9, 2020·Molecular Cancer Therapeutics·Philip N MoquistSvetlana O Doronina

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Methods Mentioned

BETA
Protein Assay
Assay

Software Mentioned

GraphPad Prism
GraphPad

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