The cAMP-signaling cancers: Clinically-divergent disorders with a common central pathway

The cAMP-signaling cancers, which are defined by functionally-significant somatic mutations in one or more elements of the cAMP signaling pathway, have an unexpectedly wide range of cell origins, clinical manifestations, and potential therapeutic options. Mutations in at least 9 cAMP signaling pathway genes (TSHR, GPR101, GNAS, PDE8B, PDE11A, PRKARA1, PRKACA, PRKACB, and CREB) have been identified as driver mutations in human cancer. Although all cAMP-signaling pathway cancers are driven by mutation(s) that impinge on a single signaling pathway, the ultimate tumor phenotype reflects interactions between five critical variables: (1) the precise gene(s) that undergo mutation in each specific tumor type; (2) the effects of specific allele(s) in any given gene; (3) mutations in modifier genes (mutational “context”); (4) the tissue-specific expression of various cAMP signaling pathway elements in the tumor stem cell; and (5) and the precise biochemical regulation of the pathway components in tumor cells. These varying oncogenic mechanisms reveal novel and important targets for drug discovery. There is considerable diversity in the “druggability” of cAMP-signaling components, with some elements (GPCRs, cAMP-specific phosphodiesterases and kinases) appearing to be prime drug candidates, while other elements (transcription factors, protein-protein interactions) are currently refractory to robust drug-development efforts. Further refinement of the precise driver mutations in individual tumors will be essential for directing priorities in drug discovery efforts that target these mutations.