GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• The Hedgehog (Hh) signaling pathway is implicated in various cancers, making it a therapeutic target.
• While mutations in Patched (PTCH) or Smoothened (SMO) drive Hh pathway activation in some cancers, the mechanisms in most tumor types, including hematological malignancies, are unclear.
• In normal physiology, Hh pathway activation leads to increased GLI1 and decreased GLI3 transcriptional repressor (GLI3R).

Purpose of the Study:

• To investigate the mechanism of Hh pathway activation in acute myeloid leukemia (AML).
• To determine the role of GLI3 transcriptional repressor (GLI3R) in AML pathogenesis and therapeutic response.
• To explore GLI3R as a potential biomarker and therapeutic target in AML.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) AML data set for gene expression and epigenetic modifications.
• Functional studies involving restoration of GLI3R in AML cells.
• Assessment of GLI3R's impact on AML cell growth and downstream signaling pathways, including AKT.

Main Results:

• The Hh pathway is active in AML, but its activation is largely independent of SMO.
• GLI3 expression is silenced in most AML samples due to abnormal methylation at the GLI3 locus.
• Restoration of GLI3R suppresses AML growth and downregulates AKT expression.
• GLI3R is essential for the efficacy of SMO antagonists in AML models.

Conclusions:

• GLI3R plays a critical role in SMO-independent Hh signaling in AML.
• GLI3R functions as a tumor suppressor in AML by downregulating AKT signaling.
• GLI3R may serve as a predictive biomarker for SMO antagonist therapy and supports combination strategies with hypomethylating agents.