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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer

Andrew D Jenks1, Simon Vyse2, Jocelyn P Wong2

  • 1Division of Cancer Therapeutics, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

Cell Reports
|June 7, 2018
PubMed

Insights

Altered primary cilia (cell structures) promote cancer drug resistance by enhancing the Hedgehog pathway. Targeting cilia length can overcome this resistance, offering new therapeutic strategies for cancer treatment.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Organelle Function

Background:

  • Primary cilia are microtubule-based cellular organelles involved in sensing mechanical and chemical signals.
  • While known to contain oncogenic molecules, the specific role of primary cilia in cancer development and progression is not fully understood.
  • Kinase inhibitors are a key class of cancer therapeutics, but acquired and de novo resistance frequently limits their efficacy.

Purpose of the Study:

  • To investigate the role of primary cilia in acquired and de novo resistance to various kinase inhibitors in cancer cells.
  • To determine if alterations in cilia number, length, or structure are associated with drug resistance.
  • To explore the functional link between cilia changes, the Hedgehog pathway, and drug resistance.

Main Methods:

  • Analysis of cilia number, length, and structural features in drug-sensitive versus drug-resistant cancer cell lines.
  • Investigation of the molecular composition of cilia in resistant cells.
  • Assessment of Hedgehog pathway activation in relation to ciliation status.
  • Manipulation of cilia length using Kif7 knockdown.
  • Genetic and pharmacological targeting of cilia length and integrity.

Main Results:

  • Resistant cancer cells exhibited increased cilia number and/or length with altered structural characteristics.
  • Changes in ciliation were associated with altered cilia molecular composition and enhanced Hedgehog pathway activation.
  • Kif7 knockdown, which affects cilia length, was sufficient to induce drug resistance in sensitive cells.
  • Targeting cilia length or integrity reversed kinase inhibitor resistance in resistant cells.

Conclusions:

  • Primary cilia length and ciliogenesis play a significant role in promoting cancer drug resistance.
  • Modulating cilia characteristics represents a potential therapeutic strategy to overcome resistance to kinase inhibitors.
  • These findings have important translational implications for cancer therapy.
Keywords:
FGFRHedgehog pathwayciliakinase inhibitorresistance

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