Stem cell-like breast cancer cells with acquired resistance to metformin are sensitive to inhibitors of NADH-dependent CtBP dimerisation

Abstract

Altered flux through major metabolic pathways is a hallmark of cancer cells, and provides opportunities for therapy. Stem cell-like cancer (SCLC) cells can cause metastasis and therapy resistance. They possess metabolic plasticity, theoretically enabling resistance to therapies targeting a specific metabolic state. The CtBP transcriptional regulators are potential therapeutic targets in highly glycolytic cancer cells, as they are activated by the glycolytic coenzyme NADH. However, SCLC cells commonly exist in an oxidative state with low rates of glycolysis. Metformin inhibits complex I of the mitochondrial electron transport chain; it can kill oxidative SCLC cells, and has anti-cancer activity in patients. SCLC cells can acquire resistance to metformin through increased glycolysis. Given the potential for long-term metformin therapy, we have studied acquired metformin resistance in cells from the claudin-low subtype of breast cancer. Cells cultured for 8 weeks in sub-IC-50 metformin concentration proliferated comparably to untreated cells, and exhibited higher rates of glucose uptake. SCLC cells were enriched in metformin-adapted cultures. These SCLC cells acquired sensitivity to multiple methods of inhibition of CtBP function, including a cyclic peptide inhibitor of NADH-induced CtBP dimerisation. Single cell mRNA sequencing identified a reprogramming of epithelial mesenchymal and stem cell gene expression in the metformin-adapted SCLC cells. These SCLC cells demonstrated an acquired dependency on one of these genes, Tenascin C. Thus, in addition to acquisition of sensitivity to glycolysis-targeting therapeutic strategies, the reprograming of gene expression in the metformin-adapted SCLC cells renders them sensitive to potential therapeutic approaches not directly linked to cell metabolism.

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Identifiers

ORCID for Arindam Banerjee: orcid.org/0000-0003-2292-4936

ORCID for Charles Birts: orcid.org/0000-0002-0368-8766

ORCID for Jonathan West: orcid.org/0000-0002-5709-6790

ORCID for Stephen Beers: orcid.org/0000-0002-3765-3342

ORCID for Matthew Rose-Zerilli: orcid.org/0000-0002-1064-5350

ORCID for Jeremy Blaydes: orcid.org/0000-0001-8525-0209

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