1. Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins
- Author
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Alexander J Martinko, Charles Truillet, Olivier Julien, Juan E Diaz, Max A Horlbeck, Gordon Whiteley, Josip Blonder, Jonathan S Weissman, Sourav Bandyopadhyay, Michael J Evans, and James A Wells
- Subjects
cancer target discovery ,antibody engineering ,oncogenic RAS ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
While there have been tremendous efforts to target oncogenic RAS signaling from inside the cell, little effort has focused on the cell-surface. Here, we used quantitative surface proteomics to reveal a signature of proteins that are upregulated on cells transformed with KRASG12V, and driven by MAPK pathway signaling. We next generated a toolkit of recombinant antibodies to seven of these RAS-induced proteins. We found that five of these proteins are broadly distributed on cancer cell lines harboring RAS mutations. In parallel, a cell-surface CRISPRi screen identified integrin and Wnt signaling proteins as critical to RAS-transformed cells. We show that antibodies targeting CDCP1, a protein common to our proteomics and CRISPRi datasets, can be leveraged to deliver cytotoxic and immunotherapeutic payloads to RAS-transformed cancer cells and report for RAS signaling status in vivo. Taken together, this work presents a technological platform for attacking RAS from outside the cell.
- Published
- 2018
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