Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins
- PMID: 29359686
- PMCID: PMC5796798
- DOI: 10.7554/eLife.31098
Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins
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.
Keywords: antibody engineering; biochemistry; cancer biology; cancer target discovery; human; mouse; oncogenic RAS.
© 2018, Martinko et al.
Conflict of interest statement
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
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References
-
- Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM, Delaney AM, Kaufman M, LePage S, Leopold WR, Przybranowski SA, Sebolt-Leopold J, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA, Smith Y, Warmus JS, Tecle H. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorganic & Medicinal Chemistry Letters. 2008;18:6501–6504. doi: 10.1016/j.bmcl.2008.10.054. - DOI - PubMed
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