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1.
Nat Med ; 24(3): 271-281, 2018 03.
Article in English | MEDLINE | ID: mdl-29400712

ABSTRACT

Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.


Subject(s)
Carcinoma, Basal Cell/drug therapy , Drug Resistance, Neoplasm/genetics , Serum Response Factor/genetics , Trans-Activators/genetics , Zinc Finger Protein GLI1/genetics , Animals , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/genetics , Hedgehog Proteins , Humans , Mice , Multiprotein Complexes/genetics , Signal Transduction , Transcriptional Activation
2.
JCI Insight ; 2(21)2017 11 02.
Article in English | MEDLINE | ID: mdl-29093271

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 Ɩ/ʎ (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/metabolism
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