Rasheed, S.A.K., Leong, H.S., Lakshmanan, M. et al. GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers. Oncogene 37, 1340–1353 (2018). https://doi.org/10.1038/s41388-017-0038-6
Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of-care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs.
This work was supported by grants from National Medical Research Council, Singapore (NMRC/BNIG/2041/2015 to SAKR, NMRC/CBRG/0044/2013 to PJC, NMRC/CSA-INV/011/2016 and NMRC/CIRG/1434/2015 to NGI). PC was supported by the Inter- disciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg. This research is supported by core funding from Institute of Molecular and Cell Biology.