BSB PhD Exit Seminar: A study of cellular amino acid homeostasis identifies novel combination therapies for cancer

Gregory Gauthier-Coles

Scientific and technological advancements in the field of cell physiology over the last thirty years have uncovered the identities and functions of over sixty solute carriers which participate in the transport of amino acids in mammalian cells. However, the precise mechanisms by which the co-expression of these transporters give rise to amino acid homeostasis in cells have remained largely undetermined. Elucidating these complex processes and interactions is critical to the understanding of how dysregulated amino acid levels arise in malignancies and may point to novel therapeutic targets in cancer, among many other diseases.

To this end, a computational model of amino acid homeostasis was constructed and validated by comparing simulated amino acid equilibria in various media against experimental data from A549 lung adenocarcinoma cells and U87-MG glioma cells. A promising degree of correlation between the computational and empirical datasets was found and the model has been used to generate new research questions and hypotheses. Among these, it outlined the sodium-coupled neutral amino acid transporter SNAT2 as a viable target for pharmacological blockade to curtail cancer cell proliferation. Consequently, a high-throughput screen for the identification of novel small molecule inhibitors of SNAT2 was conducted and yielded a shortlist of lead compounds. One such compound was found to inhibit SNAT2 in mammalian cells but showed preferential selectivity for an isoform of SNAT2, called SNAT4, when expressed in Xenopus laevis oocytes. Nevertheless, its cytotoxicity was tested in cancer cells and it was found to be well tolerated at low micromolar concentrations. However, when combined with TAP20, an inhibitor of GCN2 (a sensor of amino acid insufficiency and regulator of protein translation), synergistic effects amounting to the suppression of HPAFII pancreatic cancer cell proliferation in vitro were observed. In a related study, TAP20 was further tested for synergism with a slew of transporter, metabolic enzyme, and kinase inhibitors to identify new combination therapies in cancer. CDK inhibitors among others were found to synergise well and warrant further investigations into the mechanistic relationships underpinning these synergies. Lastly, these and other findings stress the importance of integrating metabolic fluxes and cellular signalling systems to improve upon the computational model of cellular amino acid homeostasis.