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

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Abstract

Abnormally activated Hedgehog (Hh) pathway has been linked to multiple types of cancers including medulloblastoma (MB). Current Hh-targeted drug development projects mainly focus on antagonizing the upstream oncoprotein Smoothened (Smo). However, the effectiveness of Smo inhibitors is compromised by primary and acquired resistance, which is caused by mutations of Smo or other downstream components. Here, we conducted a cellular screening of small-molecule compounds and identified ABT-737 as a selective Hh inhibitor resulting in active suppression of human Hh-dependent MB cells. Mechanistically, ABT-737 suppressed Hh signals far-downstream of Smo and Sufu at Gli transcriptional effector level. In line with this, ABT-737 potentially inhibited wild-type and drug-resistant mutant Smo. More importantly, ABT-737 also delayed the growth of drug-refractory Hh-dependent MB xenografts derived from genetically engineered mouse model in vivo. These findings identify ABT-737 as a therapeutical substance for cancers with excessive Hh signaling activity, especially for those with primary or acquired resistance to Smo inhibitors in clinic.

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Data availability

The data that support the findings of this study are available from the authors on reasonable request.

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Funding

This work was financially supported by grants from Chinese Natural Science Foundation (No. 81573452, 81773767).

Author information

Authors and Affiliations

  1. Department of Clinical Trials Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Wenjing Huang

  2. School of Medicine, Shanghai University, Shanghai, 200444, China

    Juan Wang

  3. Institute of Geriatrics (Shanghai University), The Sixth People’s Hospital of Nantong, School of Medicine, Affiliated Nantong Hospital of Shanghai University, Shanghai University, Nantong, 226011, China

    Juan Wang

  4. Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China

    Han Liu

  5. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 200031, China

    Wenfu Tan

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  1. Wenjing Huang
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  2. Han Liu
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  4. Juan Wang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by WH. The first draft of the manuscript was written by JW and WH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wenfu Tan or Juan Wang.

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All animal studies were approved by and conformed to the policies and regulations of the Animal Care and Use Committee of Shanghai University, China (Date Jul. 8, 2019 /No.2019–0020).

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Huang, W., Liu, H., Tan, W. et al. ABT-737 suppresses aberrant Hedgehog pathway and overcomes resistance to smoothened antagonists by blocking Gli. Med Oncol 39, 188 (2022). https://doi.org/10.1007/s12032-022-01794-w

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