Chemical inhibition of mtDNA transcription for treatment of cancer

ABSTRACT: Mitochondrial oxidative phosphorylation (OXPHOS) is important for cancer cell growth and the persistence of therapy-resistant cancer stem cells. Here, we have developed novel first-in-class inhibitors of mitochondrial transcription (IMTs) targeting mtDNA gene expression. We show that IMTs specifically target mitochondrial RNA polymerase (POLRMT) and we defined the IMT binding site using exome sequencing of cells rendered resistant to IMTs by chemical mutagenesis and cryo-EM. IMTs act as allosteric inhibitors of POLRMT, impairing binding of the DNA-RNA hybrid and translocation of the nascent RNA. IMT treatment impairs OXPHOS in a dose-dependent way and decreases cell viability in various tumour cells. Surprisingly, several weeks of per oral IMT treatment is well tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in human cancer xenografts. We thus show that the IMTs represent a novel promising class of drugs for tumour treatment acting by inhibition of mtDNA gene expression.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ilian Atanassov  

LAB HEAD: Nils-Göran Larsson

PROVIDER: PXD018426 | Pride | 2021-12-03

REPOSITORIES: Pride