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PLK1 phosphorylates PAX3-FOXO1 the inhibition of which triggers regression of alveolar rhabdomyosarcoma


Thalhammer, Verena; Lopez-Garcia, Laura A; Herrero Martín, David; Hecker, Regina; Laubscher, Dominik; Gierisch, Maria E; Wachtel, Marco; Bode, Peter; Nanni, Paolo; Blank, Bernd; Koscielniak, Ewa; Schäfer, Beat W (2015). PLK1 phosphorylates PAX3-FOXO1 the inhibition of which triggers regression of alveolar rhabdomyosarcoma. Cancer Research, 75(1):98-110.

Abstract

Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503 leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1-mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free and overall survival. Taken together, these preclinical studies validate the PLK1 - PAX3-FOXO1 axis as a rational target to treat alveolar rhabdomyosarcoma.

Abstract

Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503 leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1-mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free and overall survival. Taken together, these preclinical studies validate the PLK1 - PAX3-FOXO1 axis as a rational target to treat alveolar rhabdomyosarcoma.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2015
Deposited On:19 Jan 2015 15:44
Last Modified:15 Sep 2017 13:03
Publisher:American Association for Cancer Research
ISSN:0008-5472
Publisher DOI:https://doi.org/10.1158/0008-5472.CAN-14-1246
PubMed ID:25398439

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