Cancer-Related Somatic Mutations in Transmembrane Helices Alter Adenosine A1 Receptor Pharmacology

Overexpression of the adenosine A(1) receptor (A(1)AR) has been detected in various cancer cell lines. However, the role of A(1)AR in tumor development is still unclear. Thirteen A(1)AR mutations were identified in the Cancer Genome Atlas from cancer patient samples. We have investigated the pharmacology of the mutations located at the 7-transmembrane domain using a yeast system. Concentration–growth curves were obtained with the full agonist CPA and compared to the wild type hA(1)AR. H78L(3.23) and S246T(6.47) showed increased constitutive activity, while only the constitutive activity of S246T(6.47) could be reduced to wild type levels by the inverse agonist DPCPX. Decreased constitutive activity was observed on five mutant receptors, among which A52V(2.47) and W188C(5.46) showed a diminished potency for CPA. Lastly, a complete loss of activation was observed in five mutant receptors. A selection of mutations was also investigated in a mammalian system, showing comparable effects on receptor activation as in the yeast system, except for residues pointing toward the membrane. Taken together, this study will enrich the view of the receptor structure and function of A(1)AR, enlightening the consequences of these mutations in cancer. Ultimately, this may provide an opportunity for precision medicine for cancer patients with pathological phenotypes involving these mutations.