Metabolic drug survey highlights cancer cell dependencies and vulnerabilities

Tea Pemovska,Felix Kartnig,Peter Valent,Christoph Kornauth,Andreas Bergthaler,Giulio Superti-Furga,Alexander Lercher,Ismet Srndic,Johannes W Bigenzahn,Philipp B Staber,Adrián César-Razquin

doi:10.1038/s41467-021-27329-x

Abstract

Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities. To systematically study the consequences of distinct metabolic perturbations, we assemble a comprehensive metabolic drug library (CeMM Library of Metabolic Drugs; CLIMET) covering 243 compounds. We, next, characterize it phenotypically in a diverse panel of myeloid leukemia cell lines and primary patient cells. Analysis of the drug response profiles reveals that 77 drugs affect cell viability, with the top effective compounds targeting nucleic acid synthesis, oxidative stress, and the PI3K/mTOR pathway. Clustering of individual drug response profiles stratifies the cell lines into five functional groups, which link to specific molecular and metabolic features. Mechanistic characterization of selective responses to the PI3K inhibitor pictilisib, the fatty acid synthase inhibitor GSK2194069, and the SLC16A1 inhibitor AZD3965, bring forth biomarkers of drug response. Phenotypic screening using CLIMET represents a valuable tool to probe cellular metabolism and identify metabolic dependencies at large.

Highlights

Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities
The metabolic target space of these compounds was categorized to eight different processes with the majority targeting lipid and fatty acid (FA) (n = 84), protein and amino acid (n = 43), and glycolysis/sugar metabolism (n = 39) (Fig. 1d)
We describe the generation and functional characterization of a custom, focused metabolic drug library, CLIMET, as a powerful tool to identify cell-specific metabolic dependencies

Summary

Introduction

Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities. To systematically study the consequences of distinct metabolic perturbations, we assemble a comprehensive metabolic drug library (CeMM Library of Metabolic Drugs; CLIMET) covering 243 compounds We, characterize it phenotypically in a diverse panel of myeloid leukemia cell lines and primary patient cells. Genetic events activate signaling pathways that subsequently modulate cellular metabolism to satisfy the increased bioenergetic, biosynthetic and redox demands[4,5,6] This supports cancer initiation and progression and is typically accompanied with changes in expression of metabolic enzymes and transporters, which has implications for nutrient uptake, distribution of nutrients to pathways for biomass generation affecting therapy response[2,7,8]. Our data provides a primer for the use of a focused metabolic drug library in phenotypic screening platforms, thereby identifying metabolic vulnerabilities and pinpointing that targeted metabolic perturbations may provide promising new therapeutic strategies for myeloid leukemias and beyond

Methods

Results

Conclusion