Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer.
(2020) Nature Communications — Vol. 11, n° 1, p. 3701 (2020)
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- Authors
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.
- Affiliations
Université De Montréal, Montreal, Quebec, Canada Institute for Research in Immunology and Cancer (IRIC)
Citations
Aubert, L., Nandagopal, N., Steinhart, Z., Lavoie, G., Nourreddine, S., Berman, J., Saba-El-Leil, M. K., Papadopoli, D., Lin, S., Hart, T., Macleod, G., Topisirovic, I., Gaboury, L., Fahrni, C. J., Schramek, D., Meloche, S., Angers, S., & Roux, P. P. (2020). Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer. Nature Communications, 11(1), 3701. https://doi.org/10.1038/s41467-020-17549-y (Original work published 2020)