Oncotarget

Research Papers:

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, Marlous Hoogstraat, Ester Caljouw, Tessa Pierson, Jochem K.H. Spoor, Lona Zeneyedpour, Hendrikus J. Dubbink, Lennard J. Dekker, Mariëlle van der Kaaij, Jenneke Kloezeman, Lotte M.E. Berghauser Pont, Nicolle J.M. Besselink, Theo M. Luider, Jos Joore, John W. Martens, Martine L.M. Lamfers, Stefan Sleijfer and Sieger Leenstra _

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Oncotarget. 2016; 7:58435-58444. https://doi.org/10.18632/oncotarget.11205

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Abstract

Subramanian Venkatesan1, Marlous Hoogstraat2,3, Ester Caljouw4, Tessa Pierson1, Jochem K.H. Spoor1, Lona Zeneyedpour5, Hendrikus J. Dubbink6, Lennard J. Dekker5, Mariëlle van der Kaaij1, Jenneke Kloezeman1, Lotte M.E. Berghauser Pont1, Nicolle J.M. Besselink2,3,7, Theo M. Luider5, Jos Joore4, John W. Martens8,9, Martine L.M. Lamfers1, Stefan Sleijfer3,8,9, Sieger Leenstra1,10

1Department of Neurosurgery, Brain Tumor Center Erasmus MC, Rotterdam, The Netherlands

2Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

3Center for Personalized Cancer Treatment (CPCT), University Medical Center Utrecht, Utrecht, The Netherlands

4Pepscope BV, Utrecht, The Netherlands

5Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

6Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

7Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

8Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

9Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

10Department of Neurosurgery, St. Elisabeth Hospital Tilburg, Tilburg, The Netherlands

Correspondence to:

Sieger Leenstra, email: [email protected]

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.


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