Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

Léo Aubert, Neethi Nandagopal, Zachary Steinhart, Geneviève Lavoie, Sami Nourreddine, Jacob Berman, Marc K. Saba-El-Leil, David Papadopoli, Sichun Lin, Traver Hart, Graham Macleod, Ivan Topisirovic, Louis Gaboury, Christoph J. Fahrni, Daniel Schramek, Sylvain Meloche, Stephane Angers and Philippe P. Roux ()
Additional contact information
Léo Aubert: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
Neethi Nandagopal: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
Zachary Steinhart: University of Toronto
Geneviève Lavoie: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
Sami Nourreddine: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
Jacob Berman: University of Toronto
Marc K. Saba-El-Leil: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
David Papadopoli: McGill University
Sichun Lin: University of Toronto
Traver Hart: University of Texas
Graham Macleod: University of Toronto
Ivan Topisirovic: McGill University
Louis Gaboury: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
Christoph J. Fahrni: Georgia Institute of Technology
Daniel Schramek: University of Toronto
Sylvain Meloche: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
Stephane Angers: University of Toronto
Philippe P. Roux: Université de Montréal, Montreal, 2950, Chemin de la Polytechnique

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17549-y

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