Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Biology

Background:

• Oncogenic KRAS mutations are prevalent in human cancers, notably colorectal cancer (CRC).
• Targeting KRAS-mutated cancers remains a significant therapeutic challenge.
• Understanding KRAS-driven cellular alterations is crucial for identifying novel treatment strategies.

Purpose of the Study:

• To investigate the impact of oncogenic KRAS on the cell surface proteome of intestinal epithelial cells.
• To identify novel, surface-accessible therapeutic targets in KRAS-mutated CRC.
• To explore potential vulnerabilities associated with KRAS mutations.

Main Methods:

• Characterization of cell surface protein expression in KRAS-mutated versus wild-type cells.
• Cell surface-based loss-of-function screens to identify essential genes.
• Investigation of copper transport mechanisms and cellular copper acquisition.
• Assessment of ATP7A expression and function in KRAS-mutated CRC.

Main Results:

• Oncogenic KRAS significantly alters cell surface protein expression, revealing potential therapeutic targets.
• ATP7A, a copper exporter, is upregulated by mutant KRAS and essential for neoplastic growth.
• KRAS-mutated CRC cells exhibit increased surface ATP7A, conferring resistance to copper toxicity.
• Copper uptake via macropinocytosis is required for the growth of KRAS-mutated cells.

Conclusions:

• Copper bioavailability represents a KRAS-selective vulnerability in colorectal cancer.
• Targeting copper metabolism or transport could be a promising therapeutic strategy for KRAS-mutated neoplasms.
• ATP7A and copper acquisition pathways are critical for KRAS-driven tumor progression.