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 - 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
SN - 0390-6078
VL - 106
SP - 1034
EP - 1046
JO - Haematologica
JF - Haematologica
IS - 4
ER -