Concomitant targeting of Hedgehog signaling and MCL-1 synergistically induces cell death in Hedgehog-driven cancer cells

Michael Torsten Meister, Cathinka Boedicker, Benedikt Linder, Donat Kögel, Thomas Klingebiel, Simone Fulda

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the glioma-associated oncogene homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family member MCL-1 by A-1210477 synergistically induces cell death in HH-driven cancers, i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB) cells. Combined genetic and pharmacological inhibition emphasized that co-treatment of GANT61 and A-1210477 indeed relies on inhibition of GLI1 (by GANT61) and MCL-1 (by A-1210477). Mechanistic studies revealed that A-1210477 triggers the release of BIM from MCL-1 and its shuttling to BCL-xL and BCL-2. Indeed, BIM proved to be required for GANT61/A-1210477-induced cell death, as genetic silencing of BIM using siRNA significantly rescues cell death upon GANT61/A-1210477 co-treatment. Similarly, genetic silencing of NOXA results in a significant reduction of GANT61/A-1210477-mediated cell death. Also, overexpression of MCL-1 or BCL-2 significantly protects RMS cells from GANT61/A-1210477-triggered cell death. Addition of the pan-caspase inhibitor zVAD.fmk significantly decreases GANT61/A-1210477-stimulated cell demise, indicating apoptotic cell death. In conclusion, GANT61 and A-1210477 synergize to engage mitochondrial apoptosis. These findings provide the rationale for further evaluation of dual inhibition of HH signaling and MCL-1 in HH-driven cancers.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalCancer Letters
Publication statusPublished - 28 Nov 2019
Externally publishedYes


  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic/drug effects
  • Hedgehog Proteins/metabolism
  • Humans
  • Indoles/pharmacology
  • Mitochondria/drug effects
  • Myeloid Cell Leukemia Sequence 1 Protein/metabolism
  • Neoplasms/drug therapy
  • Pyridines/pharmacology
  • Pyrimidines/pharmacology
  • Signal Transduction/drug effects
  • Sulfonamides/pharmacology
  • Zinc Finger Protein GLI1/metabolism


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