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Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
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Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
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Journal Article
Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
2020
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/89
/ 14/19
/ 14/69
/ 49/47
/ 49/91
/ 64/60
/ 82/1
/ 82/51
/ 82/58
/ 96/10
/ 96/106
/ 96/95
/ Animals
/ Cancer
/ Colorectal Neoplasms - genetics
/ Colorectal Neoplasms - metabolism
/ Colorectal Neoplasms - pathology
/ Copper
/ Copper-Transporting ATPases - metabolism
/ Female
/ Humanities and Social Sciences
/ Humans
/ Intestinal Mucosa - pathology
/ Mice
/ Mutation
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Science
/ Toxicity
