The Hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia

Raoul Tibes, Aref Al-Kali, Gavin R. Oliver, Devora H. Delman, Nanna Hansen, Keerthi Bhagavatula, Jayaram Mohan, Fariborz Rakhshan, Thomas Wood, James M. Foran, Ruben A. Mesa, James M. Bogenberger

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background: Therapy and outcome for elderly acute myeloid leukemia (AML) patients has not improved for many years. Similarly, there remains a clinical need to improve response rates in advanced myelodysplastic syndrome (MDS) patients treated with hypomethylating agents, and few combination regimens have shown clinical benefit. We conducted a 5-azacytidine (5-Aza) RNA-interference (RNAi) sensitizer screen to identify gene targets within the commonly deleted regions (CDRs) of chromosomes 5 and 7, whose silencing enhances the activity of 5-Aza. Methods and results: An RNAi silencing screen of 270 genes from the CDRs of chromosomes 5 and 7 was performed in combination with 5-Aza treatment in four AML cell lines (TF-1, THP-1, MDS-L, and HEL). Several genes within the hedgehog pathway (HhP), specifically SHH, SMO, and GLI3, were identified as 5-Aza sensitizing hits. The smoothened (SMO) inhibitors LDE225 (erismodegib) and GDC0449 (vismodegib) showed moderate single-agent activity in AML cell lines. Further studies with erismodegib in combination with 5-Aza demonstrated synergistic activity with combination index (CI) values of 0.48 to 0.71 in seven AML lines. Clonogenic growth of primary patient samples was inhibited to a greater extent in the combination than with single-agent erismodegib or 5-Aza in 55 % (6 of 11) primary patient samples examined. There was no association of the 5-Aza/erismodegib sensitization potential to clinical-cytogenetic features or common myeloid mutations. Activation of the HhP, as determined by greater expression of HhP-related genes, showed less responsiveness to single-agent SMO inhibition, while synergy between both agents was similar regardless of HhP gene expression. In vitro experiments suggested that concurrent dosing showed stronger synergy than sequential dosing. Conclusions: Inhibition of the HhP with SMO inhibitors in combination with the hypomethylating agent 5-Aza demonstrates synergy in vitro and inhibits long-term repopulation capacity ex vivo in AML and MDS. A clinical trial combining 5-Aza with LDE225 (erismodegib) in MDS and AML is ongoing based on these results as well as additional publications suggesting a role for HhP signaling in myeloid disease.

Original languageEnglish (US)
Article number114
JournalJournal of Hematology and Oncology
Volume8
Issue number1
DOIs
StatePublished - Oct 20 2015
Externally publishedYes

Keywords

  • 5-azacytidine
  • Acute myeloid leukemia
  • Erismodegib
  • Hedgehog pathway/Hedgehog pathway inhibition
  • Myelodysplastic syndrome
  • SMO (smoothened) inhibitor

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

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