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Hedgehog pathway and smoothened inhibitors in cancer therapies

Kirti K Chahal1,2, Milind Parle1, Ruben Abagyan2

  • 1Department of Pharmaceutical Sciences, G.J. University of Science and Technology, Hisar, India.

Anti-Cancer Drugs
|March 15, 2018
PubMed

Insights

Targeting the hedgehog (Hh) pathway shows promise for cancers, but SMO antagonists have limited success. Combination therapies and precise patient selection are key for better cancer treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The hedgehog (Hh) pathway is crucial in cancer development, with aberrant activation in approximately 25% of all cancers.
  • Targeted Hh pathway inhibition was a promising strategy for Hh-dependent cancers.
  • Recent clinical trials with smoothened (SMO) antagonists show limited efficacy outside of basal cell carcinoma.

Purpose of the Study:

  • To explore the complexities of Hh pathway activation and resistance mechanisms in cancer.
  • To evaluate the potential of multitargeted agents or drug combinations for overcoming resistance.
  • To emphasize the need for refined patient selection criteria in clinical trials.

Main Methods:

  • Review of existing clinical trial data and molecular studies on Hh pathway signaling.
  • Analysis of Hh pathway interactions with other cellular pathways.
  • Consideration of drug resistance mechanisms in Hh-dependent cancers.

Main Results:

  • SMO antagonists alone are insufficient due to pathway complexity and interactions.
  • Multiple activation/inhibition mechanisms and inter-pathway crosstalk contribute to resistance.
  • Limited success of SMO antagonists in cancers beyond basal cell carcinoma.

Conclusions:

  • Inhibiting multiple oncogenic pathways, including Hh, via combination therapy or multitargeted agents is a promising strategy.
  • Improved patient selection based on confirmed aberrant Hh pathway activity is essential for therapeutic success.
  • Refined therapeutic strategies are needed to improve clinical outcomes and reduce resistance in Hh-dependent cancers.

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