Abstract:
:Antibody-drug conjugates (ADCs) selectively deliver chemotherapeutic agents to target cells and are important cancer therapeutics. However, the mechanisms by which ADCs are internalized and activated remain unclear. Using CRISPR-Cas9 screens, we uncover many known and novel endolysosomal regulators as modulators of ADC toxicity. We identify and characterize C18ORF8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Through comparative analysis of screens with ADCs bearing different linkers, we show that a subset of late endolysosomal regulators selectively influence toxicity of noncleavable linker ADCs. Surprisingly, we find cleavable valine-citrulline linkers can be processed rapidly after internalization without lysosomal delivery. Lastly, we show that sialic acid depletion enhances ADC lysosomal delivery and killing in diverse cancer cell types, including with FDA (US Food and Drug Administration)-approved trastuzumab emtansine (T-DM1) in Her2-positive breast cancer cells. Together, these results reveal new regulators of endolysosomal trafficking, provide important insights for ADC design and identify candidate combination therapy targets.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Tsui CK,Barfield RM,Fischer CR,Morgens DW,Li A,Smith BAH,Gray MA,Bertozzi CR,Rabuka D,Bassik MCdoi
10.1038/s41589-019-0342-2subject
Has Abstractpub_date
2019-10-01 00:00:00pages
949-958issue
10eissn
1552-4450issn
1552-4469pii
10.1038/s41589-019-0342-2journal_volume
15pub_type
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