Losers of Primary Cilia Gain the Benefit of Survival

Gladiola Goranci-Buzhala1, Elke Gabriel1, Aruljothi Mariappan1

  • 1Center for Molecular Medicine Cologne and Institute of Biochemistry I of the University of Cologne, Cologne, Germany.

Cancer Discovery
|December 7, 2017
PubMed

Insights

Medulloblastoma cells develop drug resistance by losing primary cilia when treated with the Smoothened (SMO) inhibitor sonidegib. This cilia loss, linked to mutations, creates a drug-resistant "persister-like" state.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Research

Background:

  • Medulloblastoma is a common pediatric brain tumor.
  • The Smoothened (SMO) signaling pathway is a therapeutic target in medulloblastoma.
  • Primary cilia play roles in various cellular processes, including development and signaling.

Purpose of the Study:

  • To investigate the role of primary cilia in medulloblastoma response to SMO inhibitors.
  • To identify mechanisms of drug resistance in medulloblastoma.

Main Methods:

  • Treatment of medulloblastoma cells with the SMO inhibitor sonidegib.
  • Analysis of primary cilia status and gene mutations in drug-resistant cells.
  • Assessment of drug resistance mechanisms.

Main Results:

  • Loss of primary cilia in medulloblastoma cells confers resistance to sonidegib.
  • Medulloblastoma cells lose primary cilia upon sonidegib treatment, leading to acquired resistance.
  • Cilia loss is associated with recurrent mutations in ciliogenesis genes, driving drug resistance.

Conclusions:

  • Primary cilia loss is a novel mechanism for medulloblastoma cells to acquire a "persister-like" state against SMO inhibitors.
  • Targeting ciliogenesis or restoring cilia function may overcome drug resistance in medulloblastoma.
  • Understanding this mechanism opens new avenues for medulloblastoma treatment strategies.

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