Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.
2019
Summary The plasticity of a preexisting
regulatory circuitcompromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary
leiomyomatosisrenal cell carcinoma (HLRCC) is characterized by
oxidative phosphorylation(OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are
synthetically lethalwith OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that
phosphogluconate dehydrogenase(PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo . Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP + /NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo . Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
48
References
22
Citations
NaN
KQI