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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. | ||||||||||||
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| 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. | ||||||||||||
| Molecular Profile | Treatment Approach |
|---|---|
| No data available in table | |
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|---|---|---|---|---|
| No data available in table | |||||
| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
|---|---|---|---|
| Crenolanib | Crenolanib | 78 | 6 |
| 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). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| No data available in table | |||||
| 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 | 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 | 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 | 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 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 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 | 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 | 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 |
| 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 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 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 | 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 | 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 | 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 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 |
| 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 |
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 |
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