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Ref Type Journal Article
PMID (31309543)
Authors Weisberg E, Meng C, Case AE, Sattler M, Tiv HL, Gokhale PC, Buhrlage SJ, Liu X, Yang J, Wang J, Gray N, Stone RM, Adamia S, Dubreuil P, Letard S, Griffin JD
Title Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies.
Journal British journal of haematology
Vol
Issue
Date 2019 Jul 15
URL
Abstract Text Mutations in two type-3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.

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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
Crenolanib CP-868596|CP-868,596 FLT3 Inhibitor 54 PDGFR Inhibitor (Pan) 27 Crenolanib (CP-868596) is a type III receptor tyrosine kinase inhibitor of PDGFR-alpha/beta and FLT3, which results in inhibition of downstream signaling and prevents growth in tumor cells (PMID: 22745105, PMID: 24227820, PMID: 29137311, PMID: 31309543).
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
RUNX1 - RUNX1T1 KIT N822K acute myeloid leukemia sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and growth of acute myeloid leukemia cell lines harboring KIT N822K and RUNX1-RUNX1T1 in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins FLT3 F691L hematologic cancer decreased response Crenolanib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing both FLT3 exon 14 insertions (ITD) and FLT3 F691L were less sensitive to Crenolanib-induced growth inhibition compared to cells expressing FLT3 ITD in culture (PMID: 31309543). 31309543
KIT D816V acute myeloid leukemia sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and growth of erythroleukemia cells expressing KIT D816V in culture (PMID: 31309543). 31309543
KIT D816V hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited Kit phosphorylation and growth of transformed hematologic cells expressing KIT D816V in culture (PMID: 31309543). 31309543
FLT3 D835Y hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited growth of transformed hematologic cells expressing FLT3 D835Y in culture (PMID: 31309543). 31309543
FLT3 D835Y hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3 D835Y were resistant to Nexavar (sorafenib)-induced growth inhibition in culture (PMID: 31309543). 31309543
KIT D816V hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited Kit phosphorylation and growth of transformed hematologic cells expressing KIT D816V in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
RUNX1 - RUNX1T1 KIT N822K acute myeloid leukemia decreased response Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) demonstrated reduced ability to inhibit Kit phosphorylation and growth of acute myeloid leukemia cell lines harboring KIT N822K and RUNX1-RUNX1T1 in culture compared to other kinase inhibitors (PMID: 31309543). 31309543
CBL Y371H FLT3 wild-type hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 in culture (PMID: 31309543). 31309543
CBL Q365_E366insSK FLT3 wild-type hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing both FLT3 exon 14 insertions (ITD) and FLT3 F691L in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing both FLT3 exon 14 insertions (ITD) and FLT3 F691L in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
FLT3 D835Y hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing FLT3 D835Y in culture (PMID: 31309543). 31309543
CBL Q365_E366insSK FLT3 wild-type hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 in culture (PMID: 31309543). 31309543
KIT D816V acute myeloid leukemia sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited Kit phosphorylation and growth of erythroleukemia cells expressing KIT D816V in culture (PMID: 31309543). 31309543
CBL Y371H FLT3 wild-type hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 in culture (PMID: 31309543). 31309543
RUNX1 - RUNX1T1 KIT N822K acute myeloid leukemia sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) inhibited Kit phosphorylation and growth of acute myeloid leukemia cell lines harboring KIT N822K and RUNX1-RUNX1T1 in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins acute myeloid leukemia conflicting Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited Flt3 phosphorylation and growth of acute myeloid leukemia cell lines harboring FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
FLT3 D835Y hematologic cancer resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing FLT3 D835Y were resistant to Ayvakit (avapritinib)-induced growth inhibition in culture (PMID: 31309543). 31309543
RUNX1 - RUNX1T1 KIT N822K acute myeloid leukemia sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited Kit phosphorylation and growth of acute myeloid leukemia cell lines harboring KIT N822K and RUNX1-RUNX1T1 in culture (PMID: 31309543). 31309543
KIT D816V acute myeloid leukemia sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited Kit phosphorylation and growth of erythroleukemia cells expressing KIT D816V in culture (PMID: 31309543). 31309543
CBL Y371H FLT3 wild-type hematologic cancer sensitive Midostaurin Preclinical Actionable In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 in culture, reduced leukemia burden and prolonged survival in animal models (PMID: 31309543). 31309543
KIT D816V hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) did not inhibit Kit phosphorylation or growth of transformed hematologic cells expressing KIT D816V in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins acute myeloid leukemia sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited Flt3 phosphorylation and growth of acute myeloid leukemia cell lines harboring FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins acute myeloid leukemia sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited Flt3 phosphorylation and growth of acute myeloid leukemia cell lines harboring FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
CBL Y371H FLT3 wild-type hematologic cancer decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 in culture with reduced potency compared to other kinase inhibitors (PMID: 31309543). 31309543
FLT3 exon 14 ins hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
KIT D816V hematologic cancer predicted - sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) demonstrated moderate inhibition of Kit phosphorylation and growth of transformed hematologic cells expressing KIT D816V in culture (PMID: 31309543). 31309543
KIT D816V hematologic cancer sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and growth of transformed hematologic cells expressing KIT D816V in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins acute myeloid leukemia sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) inhibited Flt3 phosphorylation and growth of acute myeloid leukemia cell lines harboring FLT3_OT exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
CBL Q365_E366insSK FLT3 wild-type hematologic cancer sensitive Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 in culture (PMID: 31309543). 31309543
KIT D816V acute myeloid leukemia resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) did not inhibit Kit phosphorylation or growth of erythroleukemia cells expressing KIT D816V in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins FLT3 F691L hematologic cancer resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing both FLT3 exon 14 insertions (ITD) and FLT3 F691L were resistant to Nexavar (sorafenib)-induced growth inhibition in culture (PMID: 31309543). 31309543
FLT3 D835Y hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing FLT3 D835Y in culture (PMID: 31309543). 31309543
RUNX1 - RUNX1T1 KIT N822K acute myeloid leukemia sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib inhibited Kit phosphorylation and growth of acute myeloid leukemia cell lines harboring KIT N822K and RUNX1-RUNX1T1 in culture (PMID: 31309543). 31309543
CBL Q365_E366insSK FLT3 wild-type hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 in culture (PMID: 31309543). 31309543
RUNX1 - RUNX1T1 KIT N822K acute myeloid leukemia decreased response Midostaurin Preclinical - Cell culture Actionable In a preclinical study, Rydapt (midostaurin) demonstrated reduced ability to inhibit Kit phosphorylation and growth of acute myeloid leukemia cell lines harboring KIT N822K and RUNX1-RUNX1T1 in culture compared to other kinase inhibitors (PMID: 31309543). 31309543
KIT D816V acute myeloid leukemia resistant Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) did not inhibit Kit phosphorylation or growth of erythroleukemia cells expressing KIT D816V in culture (PMID: 31309543). 31309543
CBL Y371H FLT3 wild-type hematologic cancer sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 in culture (PMID: 31309543). 31309543
KIT D816V hematologic cancer resistant Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) did not inhibit Kit phosphorylation or growth of transformed hematologic cells expressing KIT D816V in culture (PMID: 31309543). 31309543
KIT D816V acute myeloid leukemia predicted - sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) demonstrated moderate inhibition of Kit phosphorylation and growth of erythroleukemia cells expressing KIT D816V in culture (PMID: 31309543). 31309543
CBL Y371H FLT3 wild-type hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins FLT3 F691L hematologic cancer decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing both FLT3 exon 14 insertions (ITD) and FLT3 F691L were less sensitive to Ayvakit (avapritinib)-induced growth inhibition compared to cells expressing FLT3 ITD in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins hematologic cancer decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) in culture with reduced potency compared to other kinase inhibitors (PMID: 31309543). 31309543
CBL Q365_E366insSK FLT3 wild-type hematologic cancer sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 in culture (PMID: 31309543). 31309543
FLT3 exon 14 ins acute myeloid leukemia resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) did not inhibit Flt3 phosphorylation or growth of acute myeloid leukemia cell lines harboring FLT3 exon 14 insertions (ITD) in culture (PMID: 31309543). 31309543
CBL Q365_E366insSK FLT3 wild-type hematologic cancer decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 in culture with reduced potency compared to other kinase inhibitors (PMID: 31309543). 31309543
FLT3 exon 14 ins FLT3 F691L hematologic cancer decreased response Quizartinib Preclinical - Cell culture Actionable In a preclinical study, transformed hematologic cells expressing both FLT3 exon 14 insertions (ITD) and FLT3 F691L were less sensitive to Quizartinib (AC220)-induced growth inhibition compared to cells expressing FLT3 ITD in culture (PMID: 31309543). 31309543
FLT3 D835Y hematologic cancer sensitive Quizartinib Preclinical - Cell culture Actionable In a preclinical study, Quizartinib (AC220) inhibited growth of transformed hematologic cells expressing FLT3 D835Y in culture (PMID: 31309543). 31309543