PLK1 inhibition enhances temozolomide efficacy in IDH1 mutant gliomas

// Robert F. Koncar 1 , Zhengtao Chu 1 , Lindsey E. Romick-Rosendale 2 , Susanne I. Wells 2 , Timothy A. Chan 3 , Xiaoyang Qi 1 , El Mustapha Bahassi 1 1 Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA 2 Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 3 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Correspondence to: El Mustapha Bahassi, email: bhassiem@uc.edu Keywords: glioma, IDH1, temozolomide, PLK1, checkpoint adaptation Received: September 09, 2016 Accepted: January 04, 2017 Published: February 02, 2017 ABSTRACT Despite multimodal therapy with radiation and the DNA alkylating agent temozolomide (TMZ), malignant gliomas remain incurable. Up to 90% of grades II-III gliomas contain a single mutant isocitrate dehydrogenase 1 ( IDH1 ) allele. IDH1 mutant-mediated transformation is associated with TMZ resistance; however, there is no clinically available means of sensitizing IDH1 mutant tumors to TMZ. In this study we sought to identify a targetable mechanism of TMZ resistance in IDH1 mutant tumors to enhance TMZ efficacy. IDH1 mutant astrocytes rapidly bypassed the G2 checkpoint with unrepaired DNA damage following TMZ treatment. Checkpoint adaptation was accompanied by PLK1 activation and IDH1 mutant astrocytes were more sensitive to treatment with BI2536 and TMZ in combination (