Abstract 5409: Cetuximab downregulates lactate dehydrogenase-A, leading to inhibition of glycolysis and reversal of the Warburg effect in HNSCC cells.

Abstract

Abstract Cetuximab is an anti-human epidermal growth factor receptor (EGFR) monoclonal antibody currently approved for treatment of patients with head and neck squamous cell carcinoma (HNSCC) in combination with conventional radiotherapy and chemotherapy. Previous studies showed that cetuximab downregulates the alpha subunit of the transcription factor hypoxia-inducible factor-1 (HIF-1α) through inhibition of EGFR-mediated downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects; however, the underlying mechanism has not been established. In this study, we explored the mechanism from the perspective of cancer metabolism. HIF-1 plays a critical role in reprogramming cancer metabolism towards aerobic glycolysis (i.e., the Warburg effect), which is critically important for supplying cancer cells with the biomass needed for cell proliferation. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive cells in a HIF-1α downregulation-dependent manner. HNSCC cells with acquired resistance to cetuximab expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant conferred resistance to cetuximab-induced G1-phase cell cycle arrest, which could be overcome by knockdown of LDH-A expression. Addition of a small molecule LDH-A inhibitor markedly enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells, in which glycolysis is followed by oxidative phosphorylation in the mitochondria. These findings provide novel mechanistic insights into cetuximab-induced antitumor effects from the perspective of cancer metabolism and suggest novel strategies for enhancing the response of cancer patients to cetuximab therapy. Citation Format: Haiquan Lu, Xinqun Li, Zhen Fan. Cetuximab downregulates lactate dehydrogenase-A, leading to inhibition of glycolysis and reversal of the Warburg effect in HNSCC cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2013-5409