Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance

Abstract

The lactate transporter /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..

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

“…To confirm the functional implication of SLC16A1 in the influx of afatinib, we used the BAY-8002 derivative, a specific inhibitor of this influx transporter [ 32 ]. We first studied the cytotoxicity profile of BAY-8002 in 22Rv1 cells and found that concentrations of up to 1 mM did not have a significant impact on cell growth ( Figure S5 ).…”

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

“…A high throughput examination of over 3 million compounds measuring lactate import-dependent intracellular acidification identified BAY-8002 as a potential MCT1 inhibitor (185). Then, authors showed the antiproliferative properties in different cells lines, where Daudi and Raji cells were most affected by this compound.…”

LncRNA-SLC16A1-AS1 induces metabolic reprogramming during Bladder Cancer progression as target and co-activator of E2F1

“…From the cancer therapeutics' point of view, our findings provide new insights on potential mechanisms underlying acquired resistance of cancer cells to MCT1 inhibitors. In particular, blockade of lactate transport by inhibition of MCT1 is used as attractive treatment strategy 63 , 102 . MCT1 inhibition causes intracellular accumulation of lactate, decrease of intracellular pH, suppression of glycolysis and tumor shrinkage, while it negatively affects tumor cells that depend on lactate import to fuel OXPHOS under conditions of limited glucose availability 102 .…”

“…In particular, blockade of lactate transport by inhibition of MCT1 is used as attractive treatment strategy 63 , 102 . MCT1 inhibition causes intracellular accumulation of lactate, decrease of intracellular pH, suppression of glycolysis and tumor shrinkage, while it negatively affects tumor cells that depend on lactate import to fuel OXPHOS under conditions of limited glucose availability 102 . Although several MCT1 inhibitors lead to a decrease of tumor growth in vivo and have entered phase I/II clinical trials 68 , they fail to achieve complete regression 102 .…”