Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5843915 | Pharmacology & Therapeutics | 2015 | 9 Pages |
Abstract
The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development.
Keywords
GCKMutation cluster regionTNKSfrizzledFZDfilamentous-actinMMTVFAPGSK3βTGFABCCBPAPCTCFF-actinDVLJnkEGFRLRPCSCSTAT3HTSMCRc-Jun N-terminal kinaseFAP, Familial Adenomatous Polyposisadenomatous polyposis colidisheveledTankyrasetransforming growth factorEMTMolecular targeting therapyTNIKColorectal cancercancer stem cellWnt signalingT-cell factorlymphoid enhancer factorhigh-throughput screeningVascular endothelial growth factorVascular Endothelial Growth Factor (VEGF)LefSignal transducer and activator of transcription-3Mouse mammary tumor virusLow-density lipoprotein receptor-related proteincasein kinaseATP-binding cassetteEpithelial–mesenchymal transitionGlycogen synthase kinase 3βEpidermal growth factor receptor
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Authors
Mari Masuda, Masaaki Sawa, Tesshi Yamada,