Activation of AMPK sensitizes medulloblastoma to Vismodegib and overcomes Vismodegib-resistance

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Silpa Gampala1, GuangJun Zhang2, Chun Ju Chang3,4

  • 1Department of Pediatrics Herman B Wells Center for Pediatric Research Indiana University School of Medicine Indianapolis IN USA.

FASEB Bioadvances
|June 14, 2021
PubMed

Insights

AMPK agonists like Metformin can overcome Vismodegib resistance in medulloblastoma. Combining these drugs inhibits GLI1 activity, suppressing tumor growth in vitro and in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Vismodegib, a Smoothened antagonist, treats basal cell carcinoma and is investigated for medulloblastoma (MB).
  • A significant number of tumors exhibit resistance to Vismodegib treatment.
  • The Sonic Hedgehog (SHH) pathway is implicated in various cancers, including MB.

Purpose of the Study:

  • To investigate the efficacy of AMPK agonists in combination with Vismodegib for medulloblastoma treatment.
  • To determine if AMPK agonists can overcome Vismodegib resistance in medulloblastoma.
  • To explore the potential of combining AMPK agonists and SHH pathway inhibitors as a chemotherapeutic strategy.

Main Methods:

  • Utilized AMPK agonists (A769662 and Metformin) in combination with Vismodegib.
  • Assessed GLI1 activity inhibition.
  • Evaluated medulloblastoma cell growth suppression in vitro and in vivo.

Main Results:

  • AMPK agonists inhibited GLI1 activity.
  • Combination therapy synergistically suppressed medulloblastoma cell growth in vitro and in vivo.
  • The combination effectively overcame Vismodegib-resistant medulloblastoma.

Conclusions:

  • AMPK agonists synergize with Vismodegib to inhibit medulloblastoma growth.
  • Combining AMPK agonists (Metformin) with SHH pathway inhibitors (Vismodegib) offers a novel therapeutic approach.
  • This combination strategy is effective in overcoming Vismodegib resistance in SHH-driven cancers like medulloblastoma.
Keywords:
AMPKHedgehog pathwayMedulloblastomaMetforminVismodegib

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