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Ref Type Journal Article
PMID (36691065)
Authors Zhang Y, Wang P, Wang Y, Shen Y
Title Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia.
URL
Abstract Text Gilteritinib is the only drug approved as monotherapy for acute myeloid leukemia (AML) patients harboring FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation throughout the world. However, drug resistance inevitably develops in clinical. Sitravatinib is a multi-kinase inhibitor under evaluation in clinical trials of various solid tumors. In this study, we explored the antitumor activity of sitravatinib against FLT3-ITD and clinically-relevant drug resistance in FLT3 mutant AML.Growth inhibitory assays were performed in AML cell lines and BaF3 cells expressing various FLT3 mutants to evaluate the antitumor activity of sitravatinib in vitro. Immunoblotting was used to examine the activity of FLT3 and its downstream pathways. Molecular docking was performed to predict the binding sites of FLT3 to sitravatinib. The survival benefit of sitravatinib in vivo was assessed in MOLM13 xenograft mouse models and mouse models of transformed BaF3 cells harboring different FLT3 mutants. Primary patient samples and a patient-derived xenograft (PDX) model were also used to determine the efficacy of sitravatinib.Sitravatinib inhibited cell proliferation, induced cell cycle arrest and apoptosis in FLT3-ITD AML cell lines. In vivo studies showed that sitravatinib exhibited a better therapeutic effect than gilteritinib in MOLM13 xenograft model and BaF3-FLT3-ITD model. Unlike gilteritinib, the predicted binding sites of sitravatinib to FLT3 did not include F691 residue. Sitravatinib displayed a potent inhibitory effect on FLT3-ITD-F691L mutation which conferred resistance to gilteritinib and all other FLT3 inhibitors available, both in vitro and in vivo. Compared with gilteritinib, sitravatinib retained effective activity against FLT3 mutation in the presence of cytokines through the more potent and steady inhibition of p-ERK and p-AKT. Furthermore, patient blasts harboring FLT3-ITD were more sensitive to sitravatinib than to gilteritinib in vitro and in the PDX model.Our study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins FLT3 D835V hematologic cancer resistant Sitravatinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation with FLT3 D835V were resistant to treatment with Sitravatinib (MGCD516) in culture and in a cell line xenograft model (PMID: 36691065). 36691065
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive Sitravatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sitravatinib (MGCD516) inhibited proliferation of transformed hematologic cells expressing a FLT3-ITD mutation with FLT3 F691L in culture, and increased the median survival to 26 days vs 14.5 days in the vehicle-treated group in a cell line xenograft model (PMID: 36691065). 36691065
FLT3 exon 14 ins FLT3 Y842C hematologic cancer sensitive Sitravatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sitravatinib (MGCD516) inhibited proliferation of transformed hematologic cells expressing FLT3-ITD with FLT3 Y842C in culture, and resulted in an increased median survival compared to the vehicle-treated group (P<0.001) in a cell line xenograft model (PMID: 36691065). 36691065
FLT3 exon 14 ins hematologic cancer sensitive Sitravatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sitravatinib (MGCD516) inhibited proliferation of transformed hematologic cells expressing a FLT3-ITD mutation in culture, and increased the median survival to 26 days vs 20 days in the Xospata (gilteritinib)-treated group in a cell line xenograft model (PMID: 36691065). 36691065
FLT3 exon 14 ins FLT3 D835Y hematologic cancer resistant Sitravatinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3-ITD mutation with FLT3 D835Y were resistant to treatment with Sitravatinib (MGCD516) in culture (PMID: 36691065). 36691065
FLT3 exon 14 ins acute myeloid leukemia sensitive Sitravatinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Sitravatinib (MGCD516) inhibited proliferation and induced cell cycle arrest in acute myeloid leukemia cells harboring a FLT3-ITD mutation in culture, increased median survival to 59 days vs 30 days in the vehicle-treated group in a cell line xenograft model, and resulted in a reduced leukemia burden in patient-derived xenograft (PDX) models compared to either Xospata (gilteritinib) or Vanflyta (quizartinib) (PMID: 36691065). 36691065
FLT3 exon 14 ins FLT3 D835F hematologic cancer resistant Sitravatinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation with FLT3 D835F were resistant to treatment with Sitravatinib (MGCD516) in culture (PMID: 36691065). 36691065