Abstract
The lactate transporter SLC16A1/monocarboxylate transporter 1 (MCT1) plays a central role in tumor cell energy homeostasis. In a cell-based screen, we identified a novel class of MCT1 inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246 cancer cell lines and show that hematopoietic tumor cells, in particular diffuse large B-cell lymphoma cell lines, and subsets of solid tumor models are particularly sensitive to MCT1 inhibition. Associated markers of sensitivity were, among others, lack of MCT4 expression, low pleckstrin homology like domain family A member 2, and high pellino E3 ubiquitin protein ligase 1 expression. The antitumor effect of MCT1 inhibition was less pronounced on tumor xenografts, with tumor stasis being the maximal response. BAY-8002 significantly increased intratumor lactate levels and transiently modulated pyruvate levels. In order to address potential acquired resistance mechanisms to MCT1 inhibition, we generated MCT1 inhibitor-resistant cell lines and show that resistance can occur by upregulation of MCT4 even in the presence of sufficient oxygen, as well as by shifting energy generation toward oxidative phosphorylation. These findings provide insight into novel aspects of tumor response to MCT1 modulation and offer further rationale for patient selection in the clinical development of MCT1 inhibitors. Mol Cancer Ther; 17(11); 2285-96. ©2018 AACR.
Highlights
Tumorigenesis is associated with profound reprogramming of cellular metabolism, and numerous connections of oncogenic drivers and cancer cell metabolism have been described [1, 2]
Because MCT1 facilitates bidirectional lactate transport, we tested the effect of BAY-8002 on lactate extrusion
Due to their particular metabolic profile, i.e., aerobic glycolysis in the presence of glucose and the reliance on alternative energy sources when glucose is scarce, tumors depend on functional lactate transport across membranes
Summary
Tumorigenesis is associated with profound reprogramming of cellular metabolism, and numerous connections of oncogenic drivers and cancer cell metabolism have been described [1, 2]. The particular metabolic requirements of cancer cells may be exploited to create therapeutic strategies for combatting cancer [3]. A well-established feature of tumor metabolism is increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of oxygen and has been termed the Warburg effect [4]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). 18, 81675 Mu€nchen, Germany; and current address for J.
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