Abstract 4427: 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 cancers, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers. BRAFV600E in turn activates the kinases MEK1 and MEK2, which stimulates the MAPK pathway to promote cancer. Excitingly, ATP inhibitors of oncogenic BRAF and MEK provide a survival advantage in metastatic melanoma, an effect enhanced by combining the two inhibitors. Thus, combining multiple approaches to inhibit MAPK signaling holds great promise for the treatment of BRAF mutation-positive cancers, especially in terms of overcoming resistance. In this regard, we previously found that copper (Cu) influx enhanced MEK1 phosphorylation of its substrates ERK1/2 through a Cu-MEK1 interaction. We 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, which was rescued by expressing activated MEK5 engineered to phosphorylate ERK1/2 or 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 a BRAF inhibitor. Taken together, these results suggest that Cu-chelation therapy could be repurposed for the treatment of BRAFV600E mutation-positive cancers. Citation Format: Donita C. Brady, Matthew S. Crowe, Michelle L. Turski, G Aaron Hobbs, Apirat Chaikuad, Stefan Knapp, Sharon L. Campbell, Dennis J. Thiele, Christopher M. Counter. Copper is required for oncogenic BRAF signaling and tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4427. doi:10.1158/1538-7445.AM2014-4427