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Researchers have discovered how a powerful cancer-causing gene that drives lung, colorectal and pancreatic cancers can influence a community of proteins on the surface of cancer cells.
Their study, published in the journal eLife, reveals that cancer-causing mutations in RAS, a family of genes found in all animal cell types, creates tell-tale changes in a community of proteins on cancer cells. They show that attacking these cells from the outside-in — by targeting the altered proteins with antibodies — could be a viable therapeutic approach for previously ‘undruggable’ cancer targets.
RAS serves as a major communication hub that relays information from outside the cell to as many as 12 different signalling pathways inside the cell, including the MAPK and PI3K pathways, which then collectively induce changes to our cells. Nearly one third of all human malignancies are caused by one of the three RAS isoforms (KRAS, NRAS and HRAS) being activated by a mutation, making RAS an important focus in cancer research.
“While there are intense efforts to target signalling pathways within the cell, very little is understood about how RAS signalling can regulate the set of proteins expressed on the surface of a cell at any time,” says senior author James Wells, Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF). “More studies in this area would help us understand how mutations in RAS signalling drive malignancy, and may point to novel targets for antibody and cellular-therapy-based treatment in RAS-driven cancers.”
Wells and his team began looking into the influence of RAS signaling on the proteins present on the surface of cells. Using an analytical technique called mass spectrometry, they studied a particular cell line called MCF10A and discovered a signature of surface proteins that change when cells are transformed with a KRAS mutation called KRAS G12V, and driven by MAPK pathway signaling.
Next, the team generated a toolkit of antibodies that target seven of these RAS-induced proteins. Applying the antibodies to their targets revealed that five of the proteins are broadly distributed on cell lines harbouring KRAS mutations. A parallel study using a cell-surface CRISPRi screen — which uses CRISPR-Cas9 technology to temporarily switch off specific genes in order to investigate their function — later found that signalling proteins involved in integrin and Wnt signaling are critical to RAS-transformed cells.
Most strikingly, the researchers observed that one protein, CDCP1, was a common target in both studies. CDCP1 has previously been identified as a driver of cancer-cell growth, metastasis and tumor progression. “While our results provide a large number of interesting proteins to follow up, we decided to focus on targeting CDCP1,” explains first author Alexander Martinko, an NSF Graduate Research Fellow at UCSF. “Our antibodies did not appear to inhibit CDCP1, but we were motivated by the fact that it was over-expressed in many RAS-driven cell lines. This suggests that it could be an attractive target for an antibody-drug-conjugate treatment.”
“Overall, we’ve presented a novel technological pipeline for the discovery and application of antibodies to surface proteins regulated by cancer-causing signalling pathways,” Wells concludes. “Ultimately, we hope this pipeline can be used to attack undruggable targets, including RAS, from the outside.”
eLife aims to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open-source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust and the Knut and Alice Wallenberg Foundation. Learn more at https://elifesciences.org.
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