PhD student in Molecular Biology
Université de Montréal
Award winning publication: The Sonic Hedgehog Factor Gli1 Imparts Drug Resistance Through Inducible Glucuronidation
Published in: Nature
« Although major progress has been made in understanding mechanisms underlying resistance in cancer, there is still more to learn. While targeting the eukaryotic translation initiation factor 4E (eIF4E) with the drug ribavirin in acute myeloid leukemia (AML) patients, we identified a novel form of drug resistance. Our studies provide evidence that the Sonic Hedgehog transcription factor Gli1 drives a novel form of drug resistance utilizing phase II drug metabolism enzymes. These enzymes act to chemically modify ribavirin to a form that can no longer bind and inhibit eIF4E. Interestingly, we showed that Gli1 per se is a sufficient driver of the glucuronidation of several drugs used for the treatment of AML, including the cornerstone of treatment Cytarabine. In our patients, elevation of Gli1 and UGT1A levels were observed in patients who were primary resistant and in patients at clinical relapse. Indeed, we observed that these factors were elevated in patients treated with standard AML therapies indicating that it could be a common form of drug resistance in these patients. »
Excitingly, this new mechanism is clinically promising for AML patients where the overall survival is on average 7 months. Using the FDA approved inhibitor of the Sonic Hedgehog pathway Vismodegib, we found that targeting Gli1 eliminated ribavirin or cytarabine glucuronidation, allowed the reemergence of eIF4E-ribavirin complexes and led to renewed drug sensitivity. To date, available Gli1 inhibitors have been used for basal cell carcinomas where the Gli1 pathway is inappropriately activated. Here, we propose a new reason for targeting the Gli1 pathway to overcome Gli1 inducible drug glucuronidation. As such, a clinical trial for AML combining Vismodegib with ribavirin is scheduled to open in the near future. This mechanism of Gli1-mediated glucuronidation could also mediate therapeutic resistance in other types of cancer and could also underlie resistance to drug families other than Ribavirin and cytarabine.