Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma

TLDR

Altered cellular metabolism, particularly an increased reliance on aerobic glycolysis, is a hallmark of cancer, yet effective therapeutic targeting of glycolysis has remained elusive; targeting the overexpressed glycolytic enzyme lactate dehydrogenase (LDH) offers a promising approach. Novel LDH inhibitors reveal that Ewing sarcoma cells are highly sensitive to LDH inhibition, with EWS‑FLI1 driving LDHA expression and genetic or pharmacologic LDHA loss impairing proliferation and inducing apoptosis, establishing LDH as a viable therapeutic target.

Abstract

Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both