Department of Radiotherapy/GROW, School for Developmental Biology & Oncology and Comprehensive Cancer Centre Maastricht MUMC+, Maastricht University, Maastricht, The Netherlands.
MAASTRO Clinic, Maastricht, The Netherlands.
Oncogene. 2019 Jul;38(27):5457-5468. doi: 10.1038/s41388-019-0802-x. Epub 2019 Apr 9.
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.
T 细胞急性淋巴细胞白血病（T-ALL）是一种起源于 T 细胞前体的侵袭性癌症。尽管包括化疗和糖皮质激素在内的当前治疗方法显著提高了生存率，但 T-ALL 仍然是一种致命疾病，需要新的治疗选择。由于超过 60%的 T-ALL 病例存在致癌 NOTCH1 突变，因此针对 NOTCH1 信号的小分子抑制剂；γ-分泌酶抑制剂（GSI）正在积极研究用于治疗 T-ALL。不幸的是，GSI 的临床疗效有限且存在剂量限制毒性。我们假设通过联合使用已知药物，通过另一种机制阻断 NOTCH 活性，可能会与 GSI 协同作用，从而以较低的浓度实现同等疗效。在这里，我们表明，临床上使用的抗疟药物氯喹（CQ），一种溶酶体功能和自噬抑制剂，可降低 T-ALL 细胞活力和增殖。在 GSI 耐药的 T-ALL 细胞系中未观察到 CQ 的这种作用。从机制上讲，CQ 会破坏氧化还原平衡，诱导 dsDNA 断裂并激活 DNA 损伤反应。CQ 还会干扰致癌 NOTCH1 的细胞内运输和加工。有趣的是，我们首次表明，CQ 与 γ-分泌酶抑制联合使用对 T-ALL 具有协同治疗作用，并降低了获得细胞活力降低和增殖阻断所需的 GSI 浓度。总的来说，我们的研究结果表明，CQ 可能是一种有前途的治疗 T-ALL 的再利用药物，无论是单独使用还是与 GSI 联合使用，都能提高治疗比率。
