Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.

Mitochondrial NADP(H)-dependent dTMP biosynthesis enables tumor cell resistance to PARP inhibitors, with specifically increased mito-NADP(H) levels maintaining mitochondrial DNA integrity.

• Why it matters: Understanding how mitochondrial metabolism influences PARPi effectiveness is crucial, as resistance limits their therapeutic potential in cancer treatment. Addressing this gap could improve strategies to overcome resistance and enhance anticancer efficacy.
• What they did: The study examined tumor cells with varying responses to PARPi, revealing that in non-responsive cells, PARP inhibition boosts mitochondrial NADP(H), promoting dTMP synthesis and preventing DNA damage, through mechanisms involving PTPN1, STAT3, and FoxO1 signaling pathways.
• The result: Targeting mitochondrial NADP(H) metabolism and associated signaling pathways offers a new approach to sensitize tumors to PARPi, potentially leading to more effective combination therapies that induce mitochondrial dysfunction in resistant cancers.