RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification

Abstract

// Paulina Ćwiek 1 , Zaira Leni 1 , Fabiana Salm 1 , Valeriya Dimitrova 1 , Beata Styp-Rekowska 2 , Gianpaolo Chiriano 3 , Michael Carroll 4 , Katrin Höland 1 , Valentin Djonov 2 , Leonardo Scapozza 3 , Patrick Guiry 4 and Alexandre Arcaro 1 1 Division of Pediatric Hematology/Oncology, Bern University Hospital, Bern, Switzerland 2 Institute of Anatomy, University of Bern, Bern, Switzerland 3 Pharmaceutical Biochemistry, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland 4 Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin, Ireland Correspondence: Alexandre Arcaro, email: // Keywords : c-Myc, medulloblastoma, PCTK1, RNA interference, synthetic lethality Received : August 19, 2014 Accepted : November 06, 2014 Published : November 06, 2014 Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is associated with a poor outcome. cMYC amplification characterizes a subgroup of MB with very poor prognosis. However, there exist so far no targeted therapies for the subgroup of MB with cMYC amplification. Here we used kinome-wide RNA interference screening to identify novel kinases that may be targeted to inhibit the proliferation of c-Myc-overexpressing MB. The RNAi screen identified a set of 5 genes that could be targeted to selectively impair the proliferation of c-Myc-overexpressing MB cell lines: AKAP12 ( A-kinase anchor protein), CSNK1α1 (casein kinase 1, alpha 1), EPHA7 (EPH receptor A7) and PCTK1 (PCTAIRE protein kinase 1). When using RNAi and a pharmacological inhibitor selective for PCTK1, we could show that this kinase plays a crucial role in the proliferation of MB cell lines and the activation of the mammalian target of rapamycin (mTOR) pathway. In addition, pharmacological PCTK1 inhibition reduced the expression levels of c-Myc. Finally, targeting PCTK1 selectively impaired the tumor growth of c-Myc-overexpressing MB cells in vivo . Together our data uncover a novel and crucial role for PCTK1 in the proliferation and survival of MB characterized by cMYC amplification.