GLI1-Inducible Glucuronidation Targets a Broad Spectrum of Drugs.
Hiba Ahmad ZahreddineBiljana Culjkovic-KraljacicJadwiga GasiorekJean DuchaineKatherine L B BordenPublished in: ACS chemical biology (2019)
Cancer therapies are plagued by resistance. Previously, we discovered a novel form of cancer drug resistance where the Glioma-associated protein 1 (GLI1) elevates UGT1A glucuronidation enzymes, thereby glucuronidating cytarabine and ribavirin, leading to resistance in leukemia patients. Here, we demonstrate that GLI1 imparts resistance to ∼40 compounds, including FDA-approved drugs with disparate chemotypes ( e.g., methotrexate and venetoclax). GLI1 indirectly elevates UGT1As via the chaperone calreticulin, which is required for resistance. Further, we demonstrate that resistant cells are more sensitive to ATP inhibitors, suggesting an Achilles' heel, which could be exploited in the future. In all, we identify GLI1-inducible glucuronidation as a broad-spectrum multidrug resistance pathway.
Keyphrases
- papillary thyroid
- end stage renal disease
- acute myeloid leukemia
- high dose
- ejection fraction
- chronic kidney disease
- newly diagnosed
- squamous cell
- prognostic factors
- peritoneal dialysis
- bone marrow
- low dose
- cell death
- cell cycle arrest
- oxidative stress
- current status
- patient reported outcomes
- heat shock protein
- lymph node metastasis