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- Title
Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer.
- Authors
Aubert, Léo; Nandagopal, Neethi; Steinhart, Zachary; Lavoie, Geneviève; Nourreddine, Sami; Berman, Jacob; Saba-El-Leil, Marc K.; Papadopoli, David; Lin, Sichun; Hart, Traver; Macleod, Graham; Topisirovic, Ivan; Gaboury, Louis; Fahrni, Christoph J.; Schramek, Daniel; Meloche, Sylvain; Angers, Stephane; Roux, Philippe P.
- Abstract
Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms. The oncogene KRAS is frequently mutated in cancer, including colorectal cancer. Here, using a cell-surface proteomics approach, KRAS-mutated colorectal cancer cells are shown to express high levels of the copper transporter ATP7A, which has an essential roles in cancer cell survival and proliferation.
- Subjects
COLORECTAL cancer; CANCER cell proliferation; BIOAVAILABILITY; EPITHELIAL cells; CANCER cells; ONCOGENES
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-17549-y