Targeting RAS driven human cancer cells with antibodies to upregulated and essential cell-surface proteins

Author:

Martinko, Alexander John [ORCID]

Truillet, Charles

Julien, Olivier [ORCID]

Diaz, Juan

Horlbeck, Max A [ORCID]

Whiteley, Gordon

Blonder, Josip

Weissman, Jonathan S [ORCID]

Bandyopadhyay, Sourav [ORCID]

Evans, Michael

Wells, James A [ORCID]
Author Address

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States., Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States., Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States., Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, United States., Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States.,

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. © 2018, Martinko et al.

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