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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0214901
JournalPloS one
Volume14
Issue number9
DOIs
StatePublished - Jan 1 2019

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Medulloblastoma
Hedgehogs
Erinaceidae
leukemia
Leukemia
HhAntag691
drugs
Tumors
Cells
neoplasms
Pharmaceutical Preparations
antagonists
Neoplasms
phosphotransferases (kinases)
Heterografts
Protein-Tyrosine Kinases
Phosphotransferases
Basal Cell Carcinoma
Growth
carcinoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chahal, K. K., Li, J., Kufareva, I., Parle, M., Durden, D. L., Wechsler-Reya, R. J., ... Abagyan, R. (2019). Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. PloS one, 14(9), [e0214901]. https://doi.org/10.1371/journal.pone.0214901

Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. / Chahal, Kirti Kandhwal; Li, Jie; Kufareva, Irina; Parle, Milind; Durden, Donald L; Wechsler-Reya, Robert J.; Chen, Clark C.; Abagyan, Ruben.

In: PloS one, Vol. 14, No. 9, e0214901, 01.01.2019.

Research output: Contribution to journalArticle

Chahal, KK, Li, J, Kufareva, I, Parle, M, Durden, DL, Wechsler-Reya, RJ, Chen, CC & Abagyan, R 2019, 'Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma', PloS one, vol. 14, no. 9, e0214901. https://doi.org/10.1371/journal.pone.0214901
Chahal, Kirti Kandhwal ; Li, Jie ; Kufareva, Irina ; Parle, Milind ; Durden, Donald L ; Wechsler-Reya, Robert J. ; Chen, Clark C. ; Abagyan, Ruben. / Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. In: PloS one. 2019 ; Vol. 14, No. 9.
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