BRAFV600E-Driven Lung Adenocarcinoma Requires Copper to Sustain Autophagic Signaling and Processing

Abstract

The transition metal copper (Cu) is an essential micronutrient required for development and proliferation, but the molecular mechanisms by which Cu contributes to these processes is not fully understood. Although traditionally studied as a static cofactor critical for the function of Cu-dependent enzymes, an expanding role for Cu is emerging to include its novel function as a dynamic mediator of signaling processes through the direct control of protein kinase activity. We now appreciate that Cu directly binds to and influences MEK1/2 and ULK1/2 kinase activity, and show here that reductions in MAPK and autophagic signaling are associated with dampened growth and survival of oncogenic BRAF-driven lung adenocarcinoma cells upon loss of Ctr1. Efficient autophagy, clonogenic survival, and tumorigenesis of BRAF-mutant cells required ULK1 Cu-binding. Although treatment with canonical MAPK inhibitors resulted in the upregulation of protective autophagy, mechanistically, the Cu chelator tetrathiomolybdate (TTM) was sufficient to target both autophagic and MAPK signaling as a means to blunt BRAF-driven tumorigenic properties. These findings support leveraging Cu chelation with TTM as an alternative therapeutic strategy to impair autophagy and MAPK signaling. As traditional MAPK monotherapies initiate autophagy signaling and promote cancer cell survival. Implications: We establish that copper chelation therapy inhibits both autophagy and MAPK signaling in BRAFV600E-driven lung adenocarcinoma, thus overcoming the upregulation of protective autophagy elicited by canonical MAPK pathway inhibitors.

Cuproptosis: mechanisms and links with cancers

“…Consistent with the MAPK signaling pathway, autophagic pathway can also promote cancer cell survival and is directly affected by copper ions. In B-Raf proto-oncogene(BRAF)-driven lung adenocarcinoma cells, loss of CTR1 leads to a decrease in copper ion concentration that is directly associated with reduced function of MEK1/2 and ULK1/2, key kinases in both signaling pathways [ 57 ]. In addition to interacting directly with important proteins in the pathway, copper ions can also affect them indirectly to regulate the biological behavior of cancers.…”

Copper-Dependent Kinases and Their Role in Cancer Inception, Progression and Metastasis

“…In the context of cancer biology, the discovery of another kinase, modulated by copper and deeply involved in tumorigenesis, led to a further development of this topic in copper-related research. The same research group more recently validated the hypothesis by demonstrating that in mouse BRAF V600E -driven lung adenocarcinoma, the reduction of intracellular copper content, achieved by CTR1 deletion or by the use of the copper chelator TTM, simultaneously affected autophagic and MAPK signaling, thus leading to the reduction of lung adenocarcinoma growth [ 114 ].…”

Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

“…In lung adenocarcinoma cells driven by the BRAF, a reduction in copper ion concentration, due to the loss of CTR1, correlates with decreased activity of MEK1/2 and ULK1/2, essential kinases in these pathways [ 97 ]. Copper ions also affect the biological behavior of cancers indirectly through various pathways.…”