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Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Giulia Anichini1, Chiara Raggi2, Mirella Pastore2

  • 1Core Research Laboratory - Institute for Cancer Research and Prevention (ISPRO), Florence, Italy.

Molecular Cancer Therapeutics
|February 22, 2023
PubMed

Insights

Targeting hedgehog (HH) signaling with SMO inhibitors and WEE1 inhibitors shows promise for intrahepatic cholangiocarcinoma (iCCA) treatment. Combined inhibition effectively suppressed iCCA growth and tumor burden.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Cholangiocarcinoma (CCA), particularly intrahepatic CCA (iCCA), exhibits chemoresistance and poor prognosis, necessitating novel therapeutic strategies.
  • Aberrant hedgehog (HH) signaling is implicated in various cancers, but its specific role in iCCA requires further elucidation.
  • Understanding the function of HH pathway components like Smoothened (SMO) and transcription factors GLI1/GLI2 is crucial for iCCA treatment development.

Purpose of the Study:

  • To investigate the role of SMO, GLI1, and GLI2 in iCCA.
  • To evaluate the therapeutic potential of combined SMO and WEE1 inhibition in iCCA.
  • To determine the mechanisms underlying the efficacy of SMO inhibition and its synergy with WEE1 inhibition.

Main Methods:

  • Transcriptomic analysis of 152 human iCCA samples to assess HH pathway gene expression.
  • Genetic silencing and pharmacologic inhibition of SMO, GLI1, and GLI2 in iCCA cell lines.
  • In vitro and in vivo (xenograft) studies evaluating single and combined inhibition of SMO and WEE1 using MRT-92 and AZD-1775.

Main Results:

  • Increased expression of GLI1, GLI2, and Patched 1 (PTCH1) was observed in iCCA tissues compared to non-tumor tissues.
  • Inhibition of SMO, GLI1, and GLI2 suppressed iCCA cell growth, survival, invasiveness, and self-renewal.
  • SMO inhibition induced DNA damage, mitotic arrest, and apoptosis, activating the G2-M checkpoint and WEE1 kinase.
  • Combined inhibition of SMO (MRT-92) and WEE1 (AZD-1775) demonstrated enhanced antitumor activity in vitro and in iCCA xenografts.

Conclusions:

  • Aberrant HH signaling, mediated by SMO, GLI1, and GLI2, drives iCCA progression.
  • SMO inhibition triggers DNA damage and sensitizes iCCA cells to WEE1 inhibition.
  • The combination of SMO and WEE1 inhibitors represents a promising therapeutic strategy for iCCA, warranting further clinical investigation.

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