Study targets metabolic pathways to identify sensitivities among cancer cells

Different types of cancer show variations in their cellular metabolism contributing to the growth and progression of cancer. Metabolic reprogramming, accepted as a hallmark of cancer, might indicate a vulnerability to be used by targeted cancer therapy.

Study targets metabolic pathways to identify sensitivities among cancer cells
Tea Pemovska and Giulio Superti-Furga. Image Credit: © Klaus Pichler / CeMM.

Researchers from the group of Giulio Superti-Furga, Scientific Director at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor at the Medical University of Vienna, recently utilized a drug library of 243 compounds focusing on various metabolic pathways to pinpoint sensitivities among 15 myeloid leukemia cell lines.

The researchers could pinpoint numerous possibilities of specific pharmacological interventions.

To grow and duplicate quickly, proliferating cancer cells modify their metabolism to fulfill the increased biosynthetic and bioenergetic demand—altered metabolism being hallmark of cancer. Cancer cells rely on this “high-powered” metabolic state to survive and progress in the body and also in the cell culture.

Giulio Superti-Furga’s lab at CeMM and MedUni Vienna was experimenting on comprehending the dependency of certain functions in human cells on nutrients and metabolites for some years now.

The researchers utilized a small chemical compound library, known as CLIMET—for CeMM Library of Metabolic Drugs—for experimentally analyzing which part of the modified metabolic program is vital, and thus critical, to various cancer cell types. The library has 243 active ingredients that affect the metabolism of cells by performing on various branches of the huge, intricate and broadly connected network underlying cellular metabolism.

The results underline certain metabolic “vulnerabilities” of specific leukemia cell types, that might help formulate novel therapeutic approaches. The research was published in the Nature Communications journal.

Drug sensitivity provides important clues for therapeutic approaches

The study’s first author, Tea Pemovska, during her postdoc in the Superti-Furga laboratory at CeMM, created the metabolic drug library, cautiously selecting substances targeting individual pathways across the wide spectrum of metabolic mechanisms operating in human cells.

To gain a better insight into the molecular mechanisms involved in cancer cell metabolism, the researchers carried out a proof-of-concept survey employing CLIMET on different blood cancer cell lines and patient samples. The acquired drug sensitivity profiles enabled the stratification of myeloid leukemia cell lines in five functional groups, each determined by differential sensitivity to 18 various compounds.

The collection of chemical agents that affect different aspects of cancer metabolism provides a toolkit to functionally assess cell lines, primary samples from cancer patients, and animal models in a versatile and dose-dependent way for their particular dependence on metabolic processes.

Giulio Superti-Furga, Scientific Director, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

Giulio Superti-Furga, the study leader further states, “Through this, we can get stratify cancer cell types not only by their molecular profile but by their actual metabolic needs. It is just a showcase but suggests a practical and actionable path towards an approach that exploits these cancer cell dependencies and vulnerabilities therapeutically, typically in combination with other drugs.”

Identifying “drivers” and “vulnerabilities” of cell metabolism

Tea Pemovska, who is a scientist in the Functional Precision Hematology Group at MedUni Vienna currently along with co-workers demonstrated that some human leukemia cell lines were specifically sensitive to the fatty acid synthase inhibitor GSK2194069, the PI3K inhibitor Pictilisib, and the SLC16A1 inhibitor AZD3965.

Some myeloid leukemia cell lines, especially two chronic myeloid leukemia cells, showed high selective sensitivity to the inhibitor AZD3965, which inhibits the important lactate transporter SLC16A1. This allows conclusions to be drawn about which cells and/or patients might best respond to this agent.”

Tea Pemovska, Scientist, Functional Precision Hematology Group, Medical University of Vienna

The research also underlines the benefits of a meticulously assembled drug library with a metabolic focus to be employed in phenotypic screening platforms, enabling the identification of metabolic dependencies.

Our study just delineates the feasibility of the strategy and emphasizes the importance of teasing out vulnerabilities of cancer cells by functional assays.”

Giulio Superti-Furga, Scientific Director, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

Source:
Journal reference:

Pemovska, T., et al. (2021) Metabolic drug survey highlights cancer cell dependencies and vulnerabilities. Nature Communications. doi.org/10.1038/s41467-021-27329-x.

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