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

Gespeichert in:

Bibliographische Detailangaben
Zeitschriftentitel:	Molecular Cancer Therapeutics
Personen und Körperschaften:	Quanz, Maria, Bender, Eckhard, Kopitz, Charlotte, Grünewald, Sylvia, Schlicker, Andreas, Schwede, Wolfgang, Eheim, Ashley, Toschi, Luisella, Neuhaus, Roland, Richter, Carmen, Toedling, Joern, Merz, Claudia, Lesche, Ralf, Kamburov, Atanas, Siebeneicher, Holger, Bauser, Marcus, Hägebarth, Andrea
In:	Molecular Cancer Therapeutics, 17, 2018, 11, S. 2285-2296
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Cancer Research Oncology

Details
Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
Umfang:	2285-2296
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.mct-17-1253