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A. Torossian et al.
knockdown, which was associated with a remarkable impairment in subcutaneous tumor development. Finally, we used a combination of rapamycin and crizotinib to induce an overactivation of autophagy, which did not rely on BCL2 downregulation. We found that enhanced autophagic flux correlated with impaired cell viability but occurred independently of apoptosis, suggesting the involvement of another cell death modality. Autophagy has, indeed, been shown to provide a scaffold for the necroptotic machinery46 and also to determine the means of cell death by serving as a switch between apoptosis and necroptosis.47
Further investigations are currently under way to deci- pher whether excessive autophagy and promotion of cell death upon ALK and BCL2 downregulation in ALK-positive ALCL involve the activation of convergent and interlinked cell death pathways, including autophagy, apoptosis and necroptosis. Either way, our results provide strong evidence for a massive reduction in tumor cell viability following combined ALK and BCL2 inactivation in ALK-positive ALCL, demonstrating that the molecular targeting of BCL2 could widen the therapeutic options for these patients and potentially improve their outcome by reducing the options for cancer cell escape routes.
Acknowledgments
The authors would like to thank the Inserm and Fondation ARC pour la Recherche sur le Cancer (SGiu and EE), the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie grant agreement n. 675712 (SGiu and EE), the ANR-16-CE12-018-03 (EE) for grants. The authors also thank the Université Paul Sabatier (AT), the Ligue Nationale contre le Cancer (JF) and Labex TOUCAN/Laboratoire d’excellence Toulouse Cancer (CD) for individual fellowships. The authors thank the Anexplo-Génotoul platform, Inserm/UPS, US006/CREFRE, Toulouse, France (F. Capilla and C. Salon at the histology facility) and the flow cytometry facility of CRCT/UMR1037/Inserm/UPS/ERL5294 CNRS, Toulouse, France (M. Farcé) for their technical assis- tance. They thank Dr. G. Mitou (CRCT/ Inserm/UMR1037) for her help in the development of the mRFP-EGFP-LC3 KARPAS-299 cells, Dr S. Kermorgant (Barts Cancer Institute, London, UK) for generously providing tools and advice regarding the c-MET protein and Dr. C. Philippe (CRCT/Inserm/UMR1037/UPS) for her help with cell cycle flow cytometry analyses. They also thank Dr. R. Chiarle, Dr. S. Ducamp (Boston Children Hospital, Boston, USA), Dr. F. Meggetto and Dr. C. Joffre (CRCT/Inserm/UMR1037) for helpful discussions. English proofreading was performed by Greenland scientific proofreading.
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