TITLE: “Metabolic dependencies of ecDNA and HSR focal amplification modes and plasticity.”
ABSTRACT: The focal amplification (FA) of genes that support the uncontrolled growth and proliferation of cells (i.e., oncogenes) on homogeneous chromosomal staining regions (HSRs, chromosomal) ans extrachromosomal DNA (ecDNA) is a hallmark of resistant cancers. However, it remains an open question whether oncogene FA is affected by cellular metabolism and by the composition of the tumor microenvironment. This is important because cancers carrying oncogene focal amplifications, particularly on ecDNA, can evolve fast, and are highly malignant and difficult to treat. In this context, our group recently observed high plasticity of ecDNA+/HSR+ BRAF amplification upon combined BRAF plus MEK inhibitor (i.e., vemurafenib plus selumetinib) escalation in an in-house model of resistant melanoma. We profiled this in vitro model by metabolomics and lipidomics analysis, revealing that both FA- vs FA+, and ecDNA+ vs HSR+ cells are characterized by extensive metabolism reprogramming and substantial changes in lipid composition. Ultimately, our observations support the hypothesis that oncogene focal amplification on ecDNA and HSRs can be modulated by leveraging unique metabolic vulnerabilities.
