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The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition

Oncogene volume 38, pages 5457–5468 (2019)Cite this article

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from T-cell progenitors. Although current treatments, including chemotherapy and glucocorticoids, have significantly improved survival, T-ALL remains a fatal disease and new treatment options are needed. Since more than 60% of T-ALL cases bear oncogenic NOTCH1 mutations, small molecule inhibitors of NOTCH1 signalling; γ-secretase inhibitors (GSI), are being actively investigated for the treatment of T-ALL. Unfortunately, GSI have shown limited clinical efficacy and dose-limiting toxicities. We hypothesized that by combining known drugs, blocking NOTCH activity through another mechanism, may synergize with GSI enabling equal efficacy at a lower concentration. Here, we show that the clinically used anti-malarial drug chloroquine (CQ), an inhibitor of lysosomal function and autophagy, decreases T-ALL cell viability and proliferation. This effect of CQ was not observed in GSI-resistant T-ALL cell lines. Mechanistically, CQ impairs the redox balance, induces ds DNA breaks and activates the DNA damage response. CQ also interferes with intracellular trafficking and processing of oncogenic NOTCH1. Interestingly, we show for the first time that the addition of CQ to γ-secretase inhibition has a synergistic therapeutic effect on T-ALL and reduces the concentration of GSI required to obtain a reduction in cell viability and a block of proliferation. Overall, our results suggest that CQ may be a promising repurposed drug in the treatment of T-ALL, as a single treatment or in combination with GSI, increasing the therapeutic ratio.

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Acknowledgements

We kindly thank J. Meijerink (Erasmus MC Rotterdam, The Netherlands) for providing all T-ALL cell lines, Bristol-Myers Squibb for providing BMS-906024 and N. Mizushima for providing the pEGFP-LC3 construct. We thank Rafi Kopan (Cincinnati Children’s Hospital) for providing Notch1 constructs and J. Cordero (University of Glasgow) for help with creating and characterizing RFP tagged Notch1 cDNA’s.

Funding:

This work was supported by the European Research Council (ERC) under the European Community Seventh Framework Program (FP7/2007–13) ERC starting Grant 208259 and the Kootstra-Talent Fellowship Program 2016–7 from Maastricht-UMC + .

Author contributions:

JH, RH, MS, TH and LB performed the measurements and analysed the experimental data. JH drafted the manuscript and designed the figures under supervision of AG and MV. AG, MV, SY and KR contributed to the design and implementation of the research. All authors discussed the results and commented on the manuscript.

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  1. Department of Radiotherapy/GROW, School for Developmental Biology & Oncology and Comprehensive Cancer Centre Maastricht MUMC+, Maastricht University, Maastricht, The Netherlands

    Judith Hounjet, Roger Habets, Marco B. Schaaf, Tessa C. Hendrickx, Lydie M. O. Barbeau, Sanaz Yahyanejad, Kasper M. Rouschop, Arjan J. Groot & Marc Vooijs

  2. MAASTRO Clinic, Maastricht, The Netherlands

    Judith Hounjet

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Hounjet, J., Habets, R., Schaaf, M.B. et al. The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition. Oncogene 38, 5457–5468 (2019). https://doi.org/10.1038/s41388-019-0802-x

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