Abstract IA09: Copper is required for oncogenic BRAF signaling and tumorigenesis

Abstract

Abstract The BRAF serine/threonine kinase is mutated, typically at V600, to induce an active oncogenic state in a large fraction of melanoma, thyroid, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers. BRAFV600E activates the kinases MEK1 and MEK2, which stimulate the MAPK pathway to promote cancer. ATP inhibitors of oncogenic BRAF and MEK1/2 provide a survival advantage in metastatic melanoma, an effect enhanced by co-administering two such inhibitors. Thus, combining multiple approaches to inhibit MAPK signaling is a promising strategy to treat BRAF mutation-positive cancers. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of its substrates ERK1 and ERK2 through a Cu-MEK1 interaction. We now show here that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced MAPK signaling and oncogenic BRAFV600E-mediated tumorigenesis. Loss of tumor growth was rescued by expressing a MEK1/5 chimera that phosphorylates ERK1/2 independent of Cu or an activated ERK2. Importantly, Cu chelators used in the treatment of Wilson disease reduced tumor growth of not only BRAFV600E-transformed cells, but also cells resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat BRAFV600E mutation-positive cancers. Citation Format: Donita Brady, Matt Crowe, Michelle Turski, Aaron Hobbs, Xiaojie Yao, Apirat Chaikuad, Stefan Knapp, Kunhong Xiao, Sharon Campbell, Dennis Thiele, Chris Counter. Copper is required for oncogenic BRAF signaling and tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA09. doi: 10.1158/1557-3125.RASONC14-IA09