Targeting Adenylate Cyclase Family: New Concept of Targeted Cancer Therapy

The adenylate cyclase (ADCY) superfamily is a group of glycoproteins regulating intracellular signaling. ADCYs act as key regulators in the cyclic adenosine monophosphate (cAMP) signaling pathway and are related to cell sensitivity to chemotherapy and ionizing radiation. Many members of the superfamily are detectable in most chemoresistance cases despite the complexity and unknownness of the specific mechanism underlying the role of ADCYs in the proliferation and invasion of cancer cells. The overactivation of ADCY, as well as its upstream and downstream regulators, is implicated as a major potential target of novel anticancer therapies and markers of exceptional responders to chemotherapy. The present review focuses on the oncogenic functions of the ADCY family and emphasizes the possibility of the mediating roles of deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in ADCY as a prognostic therapeutic target in modulating resistance to chemotherapy and immunotherapy. It assesses the mediating roles of ADCY and its counterparts as stress regulators in reprogramming cancer cell metabolism and the tumor microenvironment. Additionally, the well-evaluated inhibitors of ADCY-related signaling, which are under clinical investigation, are highlighted. A better understanding of ADCY-induced signaling and deleterious nsSNPs (p.E1003K and p.R1116C) in ADCY6 provides new opportunities for developing novel therapeutic strategies in personalized oncology and new approaches to enhance chemoimmunotherapy efficacy in treating various cancers.

Automated summary

The ADCY superfamily, a group of glycoproteins regulating intracellular signaling, plays a key role in the cyclic adenosine monophosphate (cAMP) signaling pathway and is related to cell sensitivity to chemotherapy and radiation. Overactivation of ADCY and its regulators is considered a major target for anticancer therapies and markers of exceptional responders to chemotherapy. In this review, the focus is on the oncogenic functions of the ADCY family and the possibility of using harmful nsSNPs in ADCY as a prognostic therapeutic target in modulating resistance to chemotherapy and immunotherapy. The review also assesses the roles of ADCY and its counterparts as stress regulators in cancer cell metabolism and the tumor microenvironment, and highlights well-evaluated inhibitors of ADCY-related signaling that are under clinical investigation. Understanding ADCY-induced signaling and harmful nsSNPs in ADCY6 provides new opportunities for personalized oncology and enhancing chemoimmunotherapy efficacy in treating various cancers.