Copper is required for oncogenic BRAF signalling and tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• BRAF kinase mutations, particularly V600E, are oncogenic drivers in melanoma and other cancers.
• The BRAF-MEK-ERK signaling pathway (MAPK pathway) is crucial for cancer cell proliferation.
• Copper (Cu) influx was previously shown to enhance MEK1-ERK1/2 phosphorylation.

Purpose of the Study:

• To investigate the role of copper in BRAF(V600E)-driven cancer signaling and tumorigenesis.
• To explore the therapeutic potential of targeting copper transport or binding in BRAF(V600E) cancers.

Main Methods:

• Assessed the impact of CTR1 levels and MEK1 mutations on BRAF(V600E) signaling in mouse and human cell models.
• Utilized MEK1-MEK5 chimeras and active ERK2 to evaluate copper-independent signaling.
• Tested the efficacy of copper chelators in BRAF(V600E) transformed cells and resistant models.

Main Results:

• Decreased CTR1 or disrupted Cu-MEK1 interaction reduced BRAF(V600E) signaling and tumor growth.
• Copper-independent signaling restoration rescued tumor growth in Ctr1-deficient cells.
• Copper chelators inhibited tumor growth in BRAF(V600E) and BRAF inhibitor-resistant cancers.

Conclusions:

• Copper influx and MEK1 copper binding are critical for BRAF(V600E)-driven tumorigenesis.
• Copper chelation therapy shows promise as a repurposed treatment for BRAF(V600E) mutated cancers.
• Targeting copper metabolism offers a novel therapeutic strategy for BRAF-mutated cancers, including those resistant to BRAF inhibitors.