Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhabdomyosarcoma (RMS) is the most prevalent pediatric soft tissue sarcoma. Multimodal treatment including surgery and traditional chemotherapy with radiotherapy have contributed to improvements in overall survival rates. However, patients with recurrent or metastatic disease have 5-year survival rates of less than 30%. One reason for the lack of therapeutic advancement is identification and targeting of critical signaling nodes. p21-activated kinases (PAK) are a family of serine/threonine kinases downstream of multiple critical tumorigenic receptor tyrosine kinase (RTK) receptors and oncogenic regulators, including IGFR and RAS signaling, that significantly contribute to aggressive malignant phenotypes. Here we report that RMS cell lines and tumors exhibit enhanced PAK4 expression levels and activity, which are further activated by growth factors involved in RMS development. Molecular perturbation of PAK4 in multiple RMS models in vitro and in vivo resulted in inhibition of RMS development and progression. Fusion-positive and -negative RMS models were sensitive to two PAK4 small molecule inhibitors, PF-3758309 and KPT-9274, which elicited significant anti-tumor and anti-metastatic potential in several primary and metastatic in vivo models, including a relapsed RMS PDX model. Transcriptomic analysis of PAK4 targeted tumors revealed inhibition of the RAS-GTPase, Hedgehog, and Notch pathways, along with evidence of activation of anti-tumor immune response signatures. This PAK4 targeting gene signature showed prognostic significance for sarcoma patients. Overall, our results show for the first time that PAK4 is a novel and viable therapeutic target for the treatment of high-risk RMS.
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PMID:Targeting PAK4 inhibits Ras-mediated signaling and multiple oncogenic pathways in high-risk Rhabdomyosarcoma. 3316 46