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Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1034-1046
Acute Myeloid Leukemia
Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models
Raghuveer Singh Mali,1 Qi Zhang,2 Rosa Anna DeFilippis,3 Antonio Cavazos,2 Vinitha Mary Kuruvilla,2 Jayant Raman,3 Vidhi Mody,4 Edna F. Choo,4 Monique Dail,5 Neil P. Shah,3,6 Marina Konopleva,2 Deepak Sampath1o# and Elisabeth A. Lasater1#
1Department of Translational Oncology, Genentech, Inc., South San Francisco, CA; 2Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; 3Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, CA; 4Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA; 5Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA and 6Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA
#DS and EAL contributed equally as co-senior authors.
oCurrent address: Ultragenyx Pharmaceutical, Novato, CA, USA.
ABSTRACT
FLT3 internal tandem duplication (FLT3-ITD) mutations account for approximately 25% of adult acute myeloid leukemia (AML) cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory AML with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indi- rectly target both BCL-XL and MCL-1 through modulation of protein expres- sion, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ AML preclinical models and provides strong mechanistic rational for clinical studies.
Introduction
Fms-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in adult acute myeloid leukemia (AML) with internal tandem duplication (FLT3-ITD) mutations identifiable in approximately 25% of cases1 and activating tyrosine kinase domain (FLT3-TKD) mutations occurring in about 7% of cases.2 Both FLT3- ITD and FLT3-TKD are ligand-independent, constitutively activated kinases that signal through the canonical downstream pathways phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinases (RAS-MAPK)3 and broadly impact cell
Correspondence:
ELISABETH A. LASATER
lasater.elisabeth@gene.com
DEEPAK SAMPATH
dsampath@ultragenyx.com
Received: December 5, 2019. Accepted: May 14, 2020. Pre-published: May 15, 2020.
https://doi.org/10.3324/haematol.2019.244020
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