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

Kirti Kandhwal Chahal,Donald L Durden,Ruben Abagyan,Jie Li,Clark C Chen,Milind Parle,Irina Kufareva,Robert J Wechsler-Reya,Chandrabose Karthikeyan

doi:10.1371/journal.pone.0214901

Abstract

Dysregulation of the seven-transmembrane (7TM) receptor Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway contributes to the development of cancers including basal cell carcinoma (BCC) and medulloblastoma (MB). However, SMO-specific antagonists produced mixed results in clinical trials, marked by limited efficacy and high rate of acquired resistance in tumors. Here we discovered that Nilotinib, an approved inhibitor of several kinases, possesses an anti-Hh activity, at clinically achievable concentrations, due to direct binding to SMO and inhibition of SMO signaling. Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting growth of two Hh-dependent MB cell lines. It also reduced tumor growth in subcutaneous MB mouse xenograft model. These results indicate that in addition to its known activity against several tyrosine-kinase-mediated proliferative pathways, Nilotinib is a direct inhibitor of the Hh pathway. The newly discovered extension of Nilotinib’s target profile holds promise for the treatment of Hh-dependent cancers.

Highlights

Smoothened (SMO) is a component of the Hedgehog (Hh) signaling pathway which plays a fundamental role in normal embryonic development and postembryonic tissue homeostasis in eukaryotes[1]
To study downstream effects of the Hh pathway inhibition by Nilotinib and other identified drugs, we evaluated their effects on viability and neurosphere (NS) formation capacity of two Hh-dependent MB cell lines: one a patient-derived Medulloblastoma Patient Derived Xenograft (MB-PDX) line[50] and another an established DAOY line[51,52]
Discovered primarily as high-affinity specific inhibitors of BCR-ABL fusion protein, Imatinib and Nilotinib have been since shown to have extensive multi-target pharmacological profiles[34]. In addition to their primary target ABL1, both Imatinib and Nilotinib inhibit tyrosine kinases PDGFRα/β and c-Kit[34]. Both PDGFRα and c-Kit are upregulated in medulloblastoma[61], and PDGFRβ was shown to be critical for migration and invasion of medulloblastoma cells[62]

Summary

Introduction

Smoothened (SMO) is a component of the Hedgehog (Hh) signaling pathway which plays a fundamental role in normal embryonic development and postembryonic tissue homeostasis in eukaryotes[1]. SMO is a seven transmembrane (7TM) receptor that belongs to the Frizzled family[2]. SMO is normally suppressed by a 12TM receptor called Patched (PTCH1) and the suppression is lifted by binding of Patched to a secreted protein ligand Sonic Hedgehog (Shh) [3]. SMO translocates from endosomes to the primary cilium where its extracellular cysteine-rich domain (CRD) becomes exposed to a yet unknown natural ligand, proposed to be cholesterol[4].

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Results

Conclusion