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TITLE: Attacking the Cancer Surfaceome with Recombinant Antibodies

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PRESENTER:   James A. Wells, Department of Pharmaceutical Chemistry, University of California, San Francisco

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WHEN:  Thursday, April 8, 2021 – 5:00pm

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WHERE:  ZOOM – Information is in the image below.

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Abstract: The cell surface proteome (surfaceome) is the primary hub for cells to communicate with the outside world, and are major targets for immunotherapy. Oncogenes are known to cause huge changes in cells (see Figure 1). Our group has applied state-of-the-art proteomics methods to quantitatively compare the surfaceomes of oncogene transformed (KRAS, HER2, EGFR, BRAF, MEK, AKT and MYC) versus isogenic controls (1-3). Oncogenes lead to large and bi-directional remodeling of the surfaceomes of isogenic cell lines that can be exploited for target ID. Each oncogene has a unique signature that depends on cell line, but broadly similar across cell lines. Differences among related oncogenes converge when viewed at functional level by Geneset analysis. Proliferative oncogenes (EGFR, HER2, KRAS, BRAF, MEK) remodel the surfaceome primarily through MAPK pathway. MYC is much more unique, especially in the large changes induced in solute carrier proteins. We have also recently developed a technology to identify proteolytic cut sites in membrane proteins (4) which also show bi-direction remodeling. We show proteolysis is an orthogonal remodeling event, and the union with expression data offers new neo-epitope markers for immunotherapy.

1. Martinko A.J., Truillet C., Julien O., Diaz J.E., Horlbeck, M.A., Whiteley G., Blonder J., Weissman J.S., Bandyopadhyay S., Evans M.J., Wells J.A. (2018) “Targeting RAS Driven Human Cancer Cells with Antibodies to Upregulated and Essential Cell-Surface Proteins.” eLife. 2018;7:e31098
2. Leung, K. K., Wilson, G. M., Kirkemo, L. L., Riley, N. M., Coon, J. J., & Wells, J. A. (2020). Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes. PNAS 117(14), 7764–7775.
3. Chen, W., Mou, K. Y., Solomon, P., Aggarwal, R., Leung, K. K., & Wells, J. A. (2021). Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy. PNAS, 118(4), 1–11.
4. Weeks, A. M., Byrnes, J. R., Lui, I., & Wells, J. A. (2021). Mapping proteolytic neo-N termini at the surface of living cells. PNAS, 2020.02.23.961904.

Brief Bio:  Wells’ group pioneered the engineering of proteins, antibodies, and small molecules that target catalytic, allosteric, and protein-protein interaction sites; and technologies including protein phage display, alanine-scanning, engineered proteases for improved hydrolysis, bioconjugations, N-terminomics,  disulfide “tethering” (a novel site-directed fragment based approach for drug discovery), and more recently an industrialized recombinant antibody production pipeline for the proteome. These lead to important new insights into protease mechanisms, growth factor signaling, hot-spots in protein-protein interfaces, role of caspases in biology, and more recently determining how cell surfaces change in health and disease. His team was integral to several protein products including Somavert for acromegaly, Avastin for cancer, Lifitegrast for dry eye disease, and engineered proteases sold by Pfizer, Genentech, Shire and Genencor, respectively. He is an elected member of the US National Academy of Science, American Association of Arts and Science, and the National Academy of Inventors.

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