TY - JOUR
T1 - Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models
AU - Mali, Raghuveer Singh
AU - Zhang, Qi
AU - DeFilippis, Rosa Anna
AU - Cavazos, Antonio
AU - Kuruvilla, Vinitha Mary
AU - Raman, Jayant
AU - Mody, Vidhi
AU - Choo, Edna F.
AU - Dail, Monique
AU - Shah, Neil P.
AU - Konopleva, Marina
AU - Sampath, Deepak
AU - Lasater, Elisabeth A.
N1 - Funding Information:
The authors acknowledge Kyle Edgar for support on the Bliss analysis, and Aaron Logan and colleagues at the UCSF tissue bank for providing primary patient samples (supported by the UCSF Cancer Center Support Grant). The authors also acknowledge and thank the Genentech dosing core, cell line core group, animal resources personnel and veterinary staff for their assistance and contributions to this project.
Funding Information:
Venetoclax is developed in collaboration between Genentech, Inc. and AbbVie. RSM, VM, EFC, MD, DS and EAL are current or former employees of Genentech, Inc.. NPS received research funding from Bristol-Myers Squibb. MK is a consultant for AbbVie, Genentech, F. Hoffman La-Roche; served as advisory board member for F. Hoffman La-Roche and AbbVie; holds shares from Reata Pharmaceuticals; honoraria from Amgen, Abbvie, Genentech; research funding from AbbVie, Genentech, Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, Agios and Amgen. All other authors declare no conflicts of interest.
Publisher Copyright:
© 2021 Ferrata Storti Foundation
PY - 2021/4
Y1 - 2021/4
N2 - FT3 internal tandem duplication (FLT3-ITD) mutations account for pproximately 25% of adult acute myeloid leukemia (AML) cases and re 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 indirectly target both BCL-XL and MCL-1 through modulation of protein expression, 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.
AB - FT3 internal tandem duplication (FLT3-ITD) mutations account for pproximately 25% of adult acute myeloid leukemia (AML) cases and re 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 indirectly target both BCL-XL and MCL-1 through modulation of protein expression, 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85103683312&partnerID=8YFLogxK
U2 - 10.3324/haematol.2019.244020
DO - 10.3324/haematol.2019.244020
M3 - Article
C2 - 32414851
AN - SCOPUS:85103683312
VL - 106
SP - 1034
EP - 1046
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 4
ER -