Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.

ABSTRACT:

Background

Primary and posttreatment resistance to BRAF^V600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy.

Methods

We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the

SUBMITTER: de Groot E 

PROVIDER: S-EPMC8862475 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature