Abstract
Rhabdomyosarcoma (RMS) is the most common soft-tissue pediatric sarcoma. Clinical outcomes for RMS patients with relapsed or metastatic disease remain poor. Treatment options remain limited, presenting an urgent need for novel therapeutic targets. Using a high-throughput siRNA screen against the human kinome, we identified GRK5, a G-protein receptor kinase, as a novel regulator of RMS tumor cell growth and self-renewal. Through functional assays in vitro and in vivo, we show that GRK5 regulates cell cycle in a kinase-independent manner to promote RMS tumor cell growth. NFAT1 expression is regulated by GRK5 in a kinase independent manner, and loss of NFAT1 phenocopies GRK5 loss-of-function effects on the cell cycle alterations. Self-renewal of tumor propagating cells (TPCs) is thought to give rise to tumor relapse. We show that loss of GRK5 results in a significant reduction of RMS self-renewal capacity in part due to increased cell death. Treatment of human RMS xenografts in mice with CCG-215022, a GRK5-selective inhibitor, results in reduced tumor growth and self-renewal in both major subtypes of RMS. GRK5 represents a novel therapeutic target for the treatment of RMS.
Highlights
Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue cancer
Through functional assays in vitro and in vivo, we show that G-protein coupled receptor kinase 5 (GRK5) regulates cell cycle in a kinase-independent manner to promote RMS tumor cell growth
To identify potential candidate kinases that are essential for self-renewal of Embryonal rhabdomyosarcoma (ERMS), we performed a siRNA library screen against the human kinome (714 kinases) in two ERMS cell lines (RD and 381T)
Summary
There are two major subtypes of RMS, each with distinct histologic features and genetic alterations. Other RMS subtypes include spindle cell (SC/S), pleomorphic (PRMS) and those not otherwise specified (NOS). Tumor propagating cells (TPCs) are thought to be responsible for metastasis and relapse of some cancer types, such as breast and lung cancer [4,5,6,7], and possess stem cell-like characteristics that allow for the recapitulation of tumor heterogeneity in its entirety [7]. In human ERMS, CD133-positive cells have been found to possess stem-like characteristics and are resistant to standard-of-care chemotherapy [9]. Targeting stem-like features of RMS would provide novel therapeutic avenues for treating RMS disease relapse and metastasis
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