GLI1-Inducible Glucuronidation Targets a Broad Spectrum of Drugs
2019-02-14T00:00:00Z (GMT)
by
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.
Categories
License
CC BY-NC 4.0