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Multiple proteases are involved in mesothelin shedding by cancer cells

ABSTRACT: Mesothelin (MSLN) is a lineage restricted cell surface protein expressed in about 30% of human cancers and high MSLN expression is associated with poor survival in several different cancers1-4. The restricted expression of MSLN in normal tissue and its frequent expression in cancers make MSLN an excellent target for antibody-based therapies. Many clinical trials with agents targeting MSLN have been carried out but to date none of these agents have produced enough responses to obtain FDA approval4. MSLN shedding is an important factor that may contribute to the failure of these therapies, because shed MSLN acts as a decoy receptor and allows release of antibodies bound to cell-surface MSLN5,6. We have investigated the mechanism of shedding and show here that members of the ADAM, MMP and BACE families of proteases all participate in shedding, that more than one protease can produce shedding in the same cell, and that inhibition of shedding greatly enhances killing of cells by an immunotoxin targeting MSLN. Our data indicates that controlling MSLN shedding could greatly increase the activity of therapies that target MSLN.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ira Pastan

PROVIDER: MSV000085950 | MassIVE | Fri Aug 14 12:47:00 BST 2020

REPOSITORIES: MassIVE

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