TY - JOUR
T1 - Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma
AU - Chahal, Kirti Kandhwal
AU - Li, Jie
AU - Kufareva, Irina
AU - Parle, Milind
AU - Durden, Donald L.
AU - Wechsler-Reya, Robert J.
AU - Chen, Clark C.
AU - Abagyan, Ruben
N1 - Funding Information:
The project is partially funded by NIH grant R01 GM071872 (to R.A.) and 1RO1NS097649-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (to C.C.C.). The part of the project was also supported by NIH grant R01 AI118985 and R01 GM117424 (to I.K.).
Publisher Copyright:
© 2019 Chahal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072511349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072511349&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0214901
DO - 10.1371/journal.pone.0214901
M3 - Article
C2 - 31539380
AN - SCOPUS:85072511349
SN - 1932-6203
VL - 14
JO - PloS one
JF - PloS one
IS - 9
M1 - e0214901
ER -