Dissecting molecular mechanisms of resistance to NOTCH1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts

被引:11
作者
Agnusdei, Valentina [1 ]
Minuzzo, Sonia [2 ]
Pinazza, Marica [1 ]
Gasparini, Alessandra [1 ]
Pezze, Laura [3 ]
Amaro, Adriana Agnese [4 ]
Pasqualini, Lorenza [4 ]
Del Bianco, Paola [1 ]
Tognon, Martina [1 ]
Frasson, Chiara [5 ]
Palumbo, Pietro [6 ]
Ciribilli, Yari [3 ]
Pfeffer, Ulrich [4 ]
Carella, Massimo [6 ]
Amadori, Alberto [1 ,2 ]
Indraccolo, Stefano [1 ]
机构
[1] Ist Oncol Veneto IOV IRCCS, Padua, Italy
[2] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy
[3] Univ Trento, Dept Cellular Computat & Integrat Biol CIBIO, Lab Mol Canc Genet, Trento, Italy
[4] IRCCS Osped Policlin San Martino, Tumor Epigenet, Genoa, Italy
[5] Fdn Citta Speranza, Ist Ric Pediat, Padua, Italy
[6] Fdn IRCCS Casa Sollievo Sofferenza, Med Genet Unit, San Giovanni Rotondo, Italy
关键词
NOTCH; ACTIVATION; MUTATIONS; TRAFFICKING; ENDOCYTOSIS; PATHWAY; COMPLEX; SIGNAL;
D O I
10.3324/haematol.2019.217687
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Despite substantial progress in treatment of T-cell acute lymphoblastic leukemia (T-ALL), mortality remains relatively high, mainly due to primary or acquired resistance to chemotherapy. Further improvements in survival demand better understanding of TALL biology and development of new therapeutic strategies. The Notch pathway has been involved in the pathogenesis of this disease and various therapeutic strategies are currently under development, including selective targeting of NOTCH receptors by inhibitory antibodies. We previously demonstrated that the NOTCH1-specific neutralizing antibody OMP52M51 prolongs survival in TALL patient-derived xenografts bearing NOTCH1/FBW7 mutations. However, acquired resistance to OMP52M51 eventually developed and we used patient-derived xenografts models to investigate this phenomenon. Multi-level molecular characterization of TALL cells resistant to NOTCH1 blockade and serial transplantation experiments uncovered heterogeneous types of resistance, not previously reported with other Notch inhibitors. In one model, resistance appeared after 156 days of treatment, it was stable and associated with loss of Notch inhibition, reduced mutational load and acquired NOTCH1 mutations potentially affecting the stability of the heterodimerization domain. Conversely, in another model resistance developed after only 43 days of treatment despite persistent down-reation of Notch signaling and it was accompanied by modulation of lipid metabolism and reduced surface expression of NOTCH1. Our findings shed light on heterogeneous mechanisms adopted by the tumor to evade NOTCH1 blockade and support clinical implementation of antibody-based target therapy for Notch-addicted tumors.
引用
收藏
页码:1317 / 1328
页数:12
相关论文
共 36 条
[1]   Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts [J].
Agnusdei, V. ;
Minuzzo, S. ;
Frasson, C. ;
Grassi, A. ;
Axelrod, F. ;
Satyal, S. ;
Gurney, A. ;
Hoey, T. ;
Seganfreddo, E. ;
Basso, G. ;
Valtorta, S. ;
Moresco, R. M. ;
Amadori, A. ;
Indraccolo, S. .
LEUKEMIA, 2014, 28 (02) :278-288
[2]   Molecular pathogenesis of T-cell leukaemia and lymphoma [J].
Aifantis, Iannis ;
Raetz, Elizabeth ;
Buonamici, Silvia .
NATURE REVIEWS IMMUNOLOGY, 2008, 8 (05) :380-390
[3]   Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia [J].
Breit, Stephen ;
Stanulla, Martin ;
Flohr, Thomas ;
Schrappe, Martin ;
Ludwig, Wolf-Dieter ;
Tolle, Gabriele ;
Happich, Margit ;
Muckenthaler, Martina U. ;
Kulozik, Andreas E. .
BLOOD, 2006, 108 (04) :1151-1157
[4]  
Brown Kristin K, 2015, F1000Prime Rep, V7, P13, DOI 10.12703/P7-13
[5]   Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse [J].
Clappier, Emmanuelle ;
Gerby, Bastien ;
Sigaux, Francois ;
Delord, Marc ;
Touzri, Farah ;
Hernandez, Lucie ;
Ballerini, Paola ;
Baruchel, Andre ;
Pflumio, Francoise ;
Soulier, Jean .
JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (04) :653-661
[6]  
Drzazga A, 2014, ACTA POL PHARM, V71, P887
[7]   Endocytic regulation of Notch signaling [J].
Fortini, Mark E. ;
Bilder, David .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2009, 19 (04) :323-328
[8]   Notch Signaling: The Core Pathway and Its Posttranslational Regulation [J].
Fortini, Mark E. .
DEVELOPMENTAL CELL, 2009, 16 (05) :633-647
[9]   Phosphatidylcholine's functions beyond that of a membrane brick [J].
Furse, Samuel ;
de Kroon, Anton I. P. M. .
MOLECULAR MEMBRANE BIOLOGY, 2015, 32 (04) :117-119
[10]   Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL [J].
Gordon, Wendy R. ;
Roy, Monideepa ;
Vardar-Ulu, Didem ;
Garfinkel, Megan ;
Mansour, Marc R. ;
Aster, Jon C. ;
Blacklow, Stephen C. .
BLOOD, 2009, 113 (18) :4381-4390