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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	Vol	Issue	Date	Pages	Journal Short Title
British journal of haematology			2019 Jul 15	488-501	Br J Haematol

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
No data available in table

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Crenolanib	Crenolanib	78	6

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Crenolanib		CP-868596\|CP-868,596	FLT3 Inhibitor 69 PDGFR Inhibitor (Pan) 30	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).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Showing 1 to 47 of 47 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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
CBL Q365_E366insSK FLT3 wild-type	hematologic cancer	sensitive	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited growth of transformed hematologic cells expressing CBL Q365_E366insSK and wild-type FLT3 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
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
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
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
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 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
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
CBL Y371H FLT3 wild-type	hematologic cancer	sensitive	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited growth of transformed hematologic cells expressing CBL Y371H and wild-type FLT3 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	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
FLT3 D835Y	hematologic cancer	conflicting	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited growth of transformed hematologic cells expressing FLT3 D835Y 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
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
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
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
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	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
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	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 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
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	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited growth of transformed hematologic cells expressing FLT3 exon 14 insertions (ITD) 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	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
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) 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	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 exon 14 ins FLT3 F691L	hematologic cancer	resistant	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) did not inhibit 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	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 exon 14 ins FLT3 F691L	hematologic cancer	predicted - resistant	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
FLT3 exon 14 ins FLT3 F691L	hematologic cancer	resistant	Gilteritinib	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 Xospata (gilteritinib)-induced growth inhibition compared to cells expressing FLT3 ITD in culture (PMID: 31309543).	31309543
FLT3 exon 14 ins FLT3 F691L	hematologic cancer	resistant	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 Vanflyta (quizartinib)-induced growth inhibition compared to cells expressing FLT3 ITD 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
KIT D816V	hematologic cancer	resistant	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) 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
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
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	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
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
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
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	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
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
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
KIT D816V	acute myeloid leukemia	resistant	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) 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	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

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