Metabolic rewiring in cancer: Pharmacological targeting of serine/glycine synthesis addicted cancers

Metabolic rewiring is a well-established hallmark of cancer that supports tumor growth, survival and chemotherapy resistance. While normal cells often proliferate at slower rate than cancer cells and therefore have lower demands for serine and glycine, several cancer subtypes hyperactivate intracellular serine/glycine synthesis and become addicted to their own production. Examples of the latter include a significant subset of triple-negative breast cancers and T-cell acute lymphoblastic leukemias that are both currently treated with toxic intensive chemotherapy regimens. As such, this cancer-specific addiction offers an attractive drug target. Previously identified inhibitors of serine/glycine synthesis did not reach clinical trials, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. To address this need, we focused on drug repurposing with the aim to develop novel therapies that can rapidly enter the clinical practice as their safety and cost-effectiveness have been optimized before.

A repurposing library was previously screened using a yeast-based model system that specifically upregulates serine/glycine synthesis as a tolerance mechanism against sublethal antifungal stress. Using this platform, we discovered two repurposed compounds, sertraline and thimerosal, that demonstrated selective toxicity to serine/glycine synthesis addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines, while they caused no growth impairment in cancer and normal lymphoid cell lines that take up serine and glycine from their environment. Furthermore, isotope tracer metabolomics, computational docking, enzymatic assays and drug-target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase (SHMT1/2) and phosphoglycerate dehydrogenase (PHGDH), respectively. In contrast to thimerosal, for which clinical applications are limited because of a toxic mercury group in its structure, sertraline is a widely used antidepressant and might therefore be a promising adjuvant therapeutic agent. Interestingly, we demonstrated that sertraline’s anti-proliferative activity was further enhanced by mitochondrial inhibitors, such as the antimalarial artemether. Moreover, combining sertraline and artemether caused G1-S cell cycle arrest in serine/glycine synthesis addicted breast cancer cells. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts.

In conclusion, this research demonstrates that a yeast-based model system can be used as rapid and low-cost screening platform for compounds targeting serine/glycine synthesis. Furthermore, it provides molecular insights into the repurposed mode of action of the antidepressant sertraline and allows to delineate a group of cancers that is particularly sensitive to treatment with sertraline. Additionally, this work underscores the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a treatment strategy for serine/glycine synthesis addicted cancers, and confirms that doses of sertraline that are clinically used in the context of depression are sufficient to exert anticancer activity when used in combination therapy.