Targeting RAS driven human cancer cells with antibodies to upregulated and essential cell-surface proteins
- University of California, San Francisco, United States
- Frederick National Laboratory for Cancer Research, 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.
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Article and author information
Author details
Alexander John Martinko
Jonathan S Weissman
Sourav Bandyopadhyay
Funding
National Institutes of Health (CA191018)
- Alexander John Martinko
- Olivier Julien
- James A Wells
Celgene (GM097316)
- Alexander John Martinko
- James A Wells
National Institutes of Health (GM097316)
- Alexander John Martinko
- Olivier Julien
- James A Wells
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AN110806-03C) of the University of California San Francisco. Animals that were studied with PET/CT were anesthitized with a mixture of isoflurane/oxygen and humanely euthanized with CO2(g).
Copyright
© 2018, Martinko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting RAS driven human cancer cells with antibodies to upregulated and essential cell-surface proteins
eLife 7:e31098.
https://doi.org/10.7554/eLife.31098
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