Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

Abstract

Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells.

The chronic myeloid leukemia stem cell: stemming the tide of persistence

“…More recently, similar results were obtained using SMO inhibitors in human CML samples in vitro and in vivo using xenografts in immunocompromised NOD scid gamma (NSG) mice 62 .…”

“…Several studies have implicated the hedgehog pathway in the maintenance (selfrenewal) and proliferation of the LSC [60][61][62] , where Smoothened (SMO) is a critical mediator. Hedgehog binding to Patched (PTCH) activates SMO which in turn activates the transcription factor GLI1.…”

Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment

“…The targeting of the Hh pathway, known to be activated in CD34+ CP‐CML, through the inhibition of SMO using LDE225 alone or in association with nilotinib, was effective in reducing the number and the self‐renewal capacity of CML LSCs in vitro, without effects on normal HSCs . A phase I clinical trial investigated the feasibility of administration of LDE225 with nilotinib in patients with CML who have failed other TKI treatments (NCT01456676).…”

Nilotinib, an approved leukemia drug, inhibits Smoothened signaling in Hedgehog-dependent medulloblastoma

“…The effectiveness of Nilotinib in CML-CP patients can also be attributed, in part, to its anti-SMO activity reported here and its ability to inhibit CSC growth. In fact, a recent study 68 demonstrated alterations of Hh pathway gene expression in a subpopulation of CML-CP patients: the negative modulators GLI3 and SUFU genes were down-regulated and the Hh target genes CCNB2, STIL, FOXM1 and GLI1 genes were up-regulated.…”