Abstract
Mutations in components of the Hedgehog (HH) signal transduction pathway are found in the majority of basal cell carcinoma (BCC) and medulloblastoma incidents. Cancerous cells with intrinsic or acquired resistance to antagonists targeting the seven transmembrane effector Smoothened (SMO) frequently invoke alternative mechanisms for maintaining deviant activity of the GLI DNA binding proteins. Here we introduce a chemical agent that simultaneously achieves inhibition of SMO and GLI activity by direct targeting of the SMO heptahelical domain and the GLI-modifying enzymes belonging to the histone deacetylase (HDAC) family. We demonstrate a small molecule SMO-HDAC antagonist (IHR-SAHA) retains inhibitory activity for GLI transcription induced by SMO-dependent and -independent mechanisms frequently associated with cancer biogenesis. Synthetic combinatorial therapeutic agents such as IHR-SAHA that a priori disable cancer drivers and anticipated mechanisms of drug resistance could extend the duration of disease remission, and provide an alternative clinical development path for realizing combinatorial therapy modalities.
Highlights
Cellular response to the secreted HH proteins is initiated upon their binding to the multi-pass protein Patched 1 (PTCH1), a suppressor of the seven transmembrane receptor Smoothened (SMO)[1]
Despite an impressive initial response in some metastatic basal cell carcinoma (BCC) patients, durable tumor growth suppression by SMO antagonists has been elusive and few treatment options that are available to patients after progression
We examined the activity of IHR-SAHA against three cancer-related genetic alterations known to induce deviant GLI activity (Fig. 4A–C)
Summary
Cellular response to the secreted HH proteins is initiated upon their binding to the multi-pass protein Patched 1 (PTCH1), a suppressor of the seven transmembrane receptor Smoothened (SMO)[1]. The majority of the tumors that re-emerge are likely to be still dependent upon GLI transcriptional activity as determined by the appearance of mutations in SMO that prevent drug binding[7,8,9,10,11], kinase-dependent mechanisms promoting sustained GLI activity in the absence of SMO input[12,13], or GLI2 gene amplification[8,14]. The activity of GLI proteins appear to be blunted by their acetylation offering opportunities for disabling GLI activity by blocking GLI deacetylases[20]. This strategy appears to be useful in blocking the growth of medulloblastomas in preclinical models of the disease[21]. We characterize the mechanism of action for this molecule called IHR-SAHA that supports HH pathway inhibitory activity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
