ABT-737 suppresses aberrant Hedgehog pathway and overcomes resistance to smoothened antagonists by blocking Gli

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The Hedgehog (Hh) pathway is frequently activated in various cancers, including medulloblastoma (MB).
• Current therapies target the upstream Smoothened (Smo) protein, but resistance often develops due to mutations in Smo or downstream pathway components.

Purpose of the Study:

• To identify novel small-molecule compounds that inhibit the Hh pathway.
• To investigate the efficacy of identified compounds against Hh-dependent medulloblastoma, particularly in cases of resistance to Smo inhibitors.

Main Methods:

• Conducted a cellular screening of small-molecule compounds to identify Hh pathway inhibitors.
• Investigated the mechanism of action of ABT-737, focusing on its effects on downstream Hh signaling components.
• Evaluated the efficacy of ABT-737 in vitro against human MB cells and in vivo using drug-refractory MB xenografts in a mouse model.

Main Results:

• Identified ABT-737 as a selective inhibitor of the Hh pathway, suppressing human Hh-dependent MB cells.
• ABT-737 demonstrated a mechanism of action that targets Hh signaling downstream of Smo and Sufu, at the Gli transcriptional effector level.
• ABT-737 inhibited both wild-type and drug-resistant mutant Smo, and delayed tumor growth in vivo in drug-refractory MB xenografts.

Conclusions:

• ABT-737 represents a promising therapeutic agent for cancers with aberrant Hh signaling.
• This compound is particularly valuable for treating Hh-dependent cancers that exhibit primary or acquired resistance to existing Smo inhibitors.