ABSTRACT
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Æ/Ê (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.
Subject(s)
Carcinoma, Basal Cell/drug therapy , Histone Deacetylase 1/drug effects , Histone Deacetylase Inhibitors/pharmacology , Isoenzymes/drug effects , Protein Kinase C/drug effects , Skin Neoplasms/drug therapy , Allografts , Animals , Carcinoma, Basal Cell/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Computational Biology , Drug Combinations , Drug Discovery , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Hedgehogs/genetics , Hedgehogs/metabolism , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Histone Deacetylase Inhibitors/chemistry , Isoenzymes/metabolism , Mice , Mice, Knockout , Protein Kinase C/metabolism , Signal Transduction , Transcription Factors/drug effects , Transcription Factors/genetics , Zinc Finger Protein GLI1/genetics , Zinc Finger Protein GLI1/metabolismABSTRACT
Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
