Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models

Raghuveer Singh Mali, Qi Zhang, Rosa Anna DeFilippis, Antonio Cavazos, Vinitha Mary Kuruvilla, Jayant Raman, Vidhi Mody, Edna F. Choo, Monique Dail, Neil P. Shah, Marina Konopleva, Deepak Sampath, Elisabeth A. Lasater

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1034-1046
Number of pages13
JournalHaematologica
Volume106
Issue number4
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Hematology

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