Unknown

Dataset Information

0

Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists.


ABSTRACT: Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMO(D477G) medulloblastoma.

SUBMITTER: Kim J 

PROVIDER: S-EPMC3548977 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications

Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists.

Kim James J   Aftab Blake T BT   Tang Jean Y JY   Kim Daniel D   Lee Alex H AH   Rezaee Melika M   Kim Jynho J   Chen Baozhi B   King Emily M EM   Borodovsky Alexandra A   Riggins Gregory J GJ   Epstein Ervin H EH   Beachy Philip A PA   Rudin Charles M CM  

Cancer cell 20130103 1


Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that  ...[more]

Similar Datasets

| S-EPMC535705 | biostudies-literature
| S-EPMC6600918 | biostudies-literature
| S-EPMC4763541 | biostudies-literature
2021-07-08 | GSE171689 | GEO
2024-05-16 | GSE266391 | GEO