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Dual Targeting of Smoothened, a Key Regulator in the Hedgehog Pathway, and BCR-ABL1 Effectively Eradicates

Kelly A Turner1,2, Min Chen1, Katharina Rothe1,2

  • 1Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V6T 1Z3, Canada.

Cells
|October 15, 2025
PubMed

Insights

Targeting the Hedgehog (HH) pathway, specifically Smoothened (SMO), is crucial for overcoming drug resistance in chronic myeloid leukemia (CML). Inhibiting SMO sensitizes resistant stem cells to tyrosine kinase inhibitors (TKIs), offering a potential curative therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Drug resistance and cancer stem cells (CSCs) impede curative cancer treatment.
  • Chronic myeloid leukemia (CML) patients often require lifelong tyrosine kinase inhibitor (TKI) therapy due to persistent TKI-resistant leukemic stem cells (LSCs).
  • The Hedgehog (HH) pathway, particularly Smoothened (SMO), is implicated in LSC maintenance, but its role in TKI resistance is unclear.

Purpose of the Study:

  • To investigate the role of the HH pathway, specifically SMO and GLI2, in TKI-resistant CML stem/progenitor cells.
  • To evaluate the therapeutic potential of SMO inhibition in overcoming TKI resistance in CML.
  • To explore combination therapy strategies involving SMO inhibitors and TKIs for CML.

Main Methods:

  • Transcriptome profiling and quantitative reverse transcription PCR (qRT-PCR) to analyze HH pathway gene expression (SMO, GLI2) in CML stem/progenitor cells.
  • Genetic knockdown of SMO and pharmacological inhibition using the SMO inhibitor Glasdegib.
  • In vitro and in vivo (patient-derived xenotransplantation model) studies to assess the effects of SMO inhibition on cell survival and TKI sensitivity.

Main Results:

  • Increased expression of HH pathway genes SMO and GLI2 was observed in CD34+ CML stem/progenitor cells compared to healthy cells.
  • Gene expression was higher in TKI-nonresponders than responders, with highest expression in LSCs from nonresponders.
  • SMO inhibition (Glasdegib) reduced survival of cells from nonresponder patients and sensitized TKI-nonresponder stem/progenitor cells to Bostutinib.

Conclusions:

  • The Hedgehog pathway, particularly SMO, is a critical driver of TKI resistance in CML stem cells.
  • SMO inhibition represents a promising therapeutic target for overcoming drug resistance in CML.
  • Combination therapy with SMO inhibitors and TKIs offers a potential strategy for curative treatment of stem-cell-driven CML.
Keywords:
BostutinibGlasdegib (PF-04449913)Hedgehog pathwaySmoothenedchronic myeloid leukemialeukemic stem cellstherapy-resistancetyrosine kinase inhibitors

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