GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers.
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.
Rasheed, SAK; Leong, HS; Lakshmanan, M; Raju, A; Dadlani, D; Chong, F-T; Shannon, NB; Rajarethinam, R; Skanthakumar, T; Tan, EY; Hwang, JSG; Lim, KH; Tan, DS-W; Ceppi, P; Wang, M; Tergaonkar, V; Casey, PJ; Iyer, NG
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