p21-activated kinases as viable therapeutic targets for the treatment of high-risk Ewing sarcoma

• Published in: Oncogene Vol. 40; no. 6; pp. 1176 - 1190
• Main Authors: Qasim, Shawki L., Sierra, Laura, Shuck, Ryan, Kurenbekova, Lyazat, Patel, Tajhal D., Rajapakshe, Kimal, Wulff, Jade, Nakahata, Kengo, Kim, Ha Ram, Landesman, Yosef, Unger, T. J., Coarfa, Cristian, Yustein, Jason T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.02.2021; Nature Publishing Group
• Subjects: 13/106; 13/95; 38/89; 38/91; 631/67/1059/602; 631/67/1798; 64/60; Acrylamides - pharmacology; Aminopyridines - pharmacology; Apoptosis; Apoptosis - drug effects; Bone tumors; Care and treatment; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell viability; Development and progression; Ewing's sarcoma; Ewings sarcoma; Fractures; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Hypoxia; Informatics; Interferon-alpha - genetics; Interferon-gamma - genetics; Internal Medicine; Invasiveness; Medicine; Medicine & Public Health; Metastases; Metastasis; Oncology; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - genetics; Patients; Phosphotransferases; Pyrazoles - pharmacology; Pyrroles - pharmacology; Risk assessment; Sarcoma; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - genetics; Sarcoma, Ewing - pathology; Signal Transduction - drug effects; Therapeutic applications; Xenograft Model Antitumor Assays; Xenografts; Young adults; α-Interferon; β-Catenin; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01600-9

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults. Unfortunately, there have been minimal recent advancements in improving patient outcomes, especially in metastatic and recurrent diseases. In this study, we investigated the biological role of p21-activated kinases (PAKs) in ES, and the ability to therapeutically target them in high-risk disease. Via informatics analysis, we established the inverse association of PAK1 and PAK4 expression with clinical stage and outcome in ES patients. Through expression knockdown and small-molecule inhibition of PAKs, utilizing FRAX-597, KPT-9274, and PF-3758309 in multiple ES cell lines and patient-derived xenograft models, we further explored the role of PAKs in ES tumor growth and metastatic capabilities. In vitro studies in several ES cell lines indicated that diminishing PAK1 and PAK4 expression reduces tumor cell viability, migratory, and invasive properties. In vivo studies using PAK4 inhibitors, KPT-9274 and PF-3758309 demonstrated significant inhibition of primary and metastatic tumor formation, while transcriptomic analysis of PAK4-inhibitor-treated tumors identified concomitant suppression of Notch, β-catenin, and hypoxia-mediated signatures. In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-ɣ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future.