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

Autor:	Martinko AJ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States., Truillet C; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States., Julien O; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States., Diaz JE; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States., Horlbeck MA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States., Whiteley G; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, United States., Blonder J; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, United States., Weissman JS; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States., Bandyopadhyay S; Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States., Evans MJ; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States., Wells JA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Jan 23; Vol. 7. Date of Electronic Publication: 2018 Jan 23.
DOI:	10.7554/eLife.31098
Abstrakt:	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 KRAS G12V , 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. Competing Interests: AM, CT, OJ, JD, MH, GW, JB, JW, SB, ME No competing interests declared, JW Celgene Corp provided some of the funding for this work (© 2018, Martinko et al.)
Databáze:	MEDLINE
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