Page 157 - Haematologica May 2020

Acute Lymphoblastic Leukemia
Dissecting molecular mechanisms of resistance to NOTCH1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5)1317-1328
Valentina Agnusdei,1 Sonia Minuzzo,2 Marica Pinazza,1 Alessandra Gasparini,1 Laura Pezzè,3 Adriana Agnese Amaro,4 Lorenza Pasqualini,1$ Paola Del Bianco,1 Martina Tognon,1 Chiara Frasson,5 Pietro Palumbo,6 Yari Ciribilli,3 Ulrich Pfeffer,4 Massimo Carella,6 Alberto Amadori1,2 and Stefano Indraccolo1
1Istituto Oncologico Veneto IOV - IRCCS, Padova; 2Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova; 3Laboratory of Molecular Cancer Genetics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento; 4Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Genova; 5Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova and 6Medical Genetics Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
$Current address: Diagnostics and genomics group, Agilent Technologies Inc. Santa Clara, CA, USA
ABSTRACT
Despite substantial progress in treatment of T-cell acute lymphoblas- tic leukemia (T-ALL), mortality remains relatively high, mainly due to primary or acquired resistance to chemotherapy. Further improvements in survival demand better understanding of T-ALL 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 sur- vival in TALL patient-derived xenografts bearing NOTCH1/FBW7 muta- tions. However, acquired resistance to OMP52M51 eventually developed and we used patient-derived xenografts models to investigate this phenom- enon. Multi-level molecular characterization of T-ALL cells resistant to NOTCH1 blockade and serial transplantation experiments uncovered het- erogeneous 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-regula- tion 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.
Introduction
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological dis- ease that results from clonal expansion of transformed lymphoid progenitors at different developmental stages.1 Cure rates for pediatric ALL are currently approx- imately 90%, but prognosis for children who experienced relapse remains poor, and it has only marginally improved over the past two decades. Therefore, more efforts are required for patients with chemotherapy-resistant leukemia to identify effective treatment strategies.2,3
The Notch pathway plays a crucial role in T-cell lineage specification and thymic development and its deregulated activation has been linked to T-ALL development and maintenance.1,4 Notably, about 50-60% of T-ALL samples show
Correspondence:
STEFANO INDRACCOLO
stefano.indraccolo@unipd.it
Received: February 8, 2019. Accepted: August 26, 2019. Pre-published: August 29, 2019.
doi:10.3324/haematol.2019.217687
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1317
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