TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2

// Subramanian Venkatesan 1 , Marlous Hoogstraat 2, 3 , Ester Caljouw 4 , Tessa Pierson 1 , Jochem K.H. Spoor 1 , Lona Zeneyedpour 5 , Hendrikus J. Dubbink 6 , Lennard J. Dekker 5 , Marielle van der Kaaij 1 , Jenneke Kloezeman 1 , Lotte M.E. Berghauser Pont 1 , Nicolle J.M. Besselink 2, 3, 7 , Theo M. Luider 5 , Jos Joore 4 , John W. Martens 8, 9 , Martine L.M. Lamfers 1 , Stefan Sleijfer 3, 8, 9 , Sieger Leenstra 1, 10 1 Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands 2 Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands 3 Center for Personalized Cancer Treatment (CPCT), University Medical Center Utrecht, Utrecht, The Netherlands 4 Pepscope BV, Utrecht, The Netherlands 5 Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands 6 Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands 7 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands 8 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands 9 Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Rotterdam, The Netherlands 10 Department of Neurosurgery, St. Elisabeth Hospital Tilburg, Tilburg, The Netherlands Correspondence to: Sieger Leenstra, email: s.leenstra@erasmusmc.nl Keywords: brain tumor, personalized medicine, genetic biomarkers, small molecule kinase inhibitors, resistance Received: January 11, 2016     Accepted: July 26, 2016     Published: August 11, 2016 ABSTRACT Background: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs). Results: We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged. Conclusion: Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored.