2. Academic Validation
  3. CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-b Signaling

CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-b Signaling

  • Cancers (Basel). 2020 Jun 30;12(7):1737. doi: 10.3390/cancers12071737.
Bo-Reum Kim 1,  Seung-Hyun Jung 2 3,  A-Reum Han 1,  Gyeongsin Park 4,  Hee-Je Kim 1 5,  Bin Yuan 6,  Venkata Lokesh Battula 6,  Michael Andreeff 6,  Marina Konopleva 7,  Yeun-Jun Chung 3,  Byung-Sik Cho 1 5 6
Affiliations

Affiliations

  • 1 Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
  • 2 Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
  • 3 Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
  • 4 Department of Pathology, College of Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
  • 5 Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
  • 6 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7 Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
PMID: 32629802 DOI: 10.3390/cancers12071737
Abstract

Given the proven importance of the CXCL12/CXCR4 axis in the stroma-acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 Inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 Inhibitor, induced Apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing Apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-b signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-b in stromal cells or TGF-b-receptor kinase inhibitor enhanced Apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-b signaling.

Keywords

CXCR4; FLT3-ITD; LY2510924; acute myeloid leukemia; quizartinib.

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