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Ref Type

Journal Article

PMID

(33149267)

Authors

Rummelt C, Gorantla SP, Meggendorfer M, Charlet A, Endres C, Döhner K, Heidel FH, Fischer T, Haferlach T, Duyster J, von Bubnoff N

Title

Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia			2020 Nov 04	2017-2029	Leukemia

URL

Abstract Text

An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB-STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FLT3	R834_D835del	deletion	unknown	FLT3 R834_D835del results in the deletion of two amino acids in the protein kinase domain of the Flt3 protein from amino acids 834 to 835 (UniProt.org). R834_D835del has been identified in sequencing studies (PMID: 31471587, PMID: 33149267), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Nov 2024).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins JAK3 R953*	acute myeloid leukemia	predicted - resistant	Quizartinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with acute myeloid leukemia harboring a FLT3-ITD mutation treated with Vanflyta (quizartinib) was found to have acquired a JAK3 R953* mutation upon relapse (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	acute myeloid leukemia	predicted - resistant	Sorafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with acute myeloid leukemia harboring a FLT3-ITD mutation treated with Nexavar (sorafenib) was found to have acquired a JAK3 V722I mutation with a variant allele frequency of 49% upon relapse (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	predicted - sensitive	Pacritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vonjo (pacritinib) treatment decreased cell proliferation and downstream signaling in transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F in culture but may not be capable of fully inhibiting Flt3 and Jak signaling at clinically achievable concentrations (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	sensitive	Gilteritinib + Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Xospata (gilteritinib) and Jakafi (ruxolitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	decreased response	Midostaurin + Tofacitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F demonstrated a decreased response to treatment with the combination of Rydapt (midostaurin) and Xeljanz (tofacitinib) compared to cells expressing a FLT3-ITD mutation and activating mutations of JAK1 or JAK3 in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	sensitive	Midostaurin + Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited downstream signaling and cell growth in transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	resistant	Tofacitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Xeljanz (tofacitinib) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	resistant	Gilteritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Xospata (gilteritinib) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	resistant	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK2 V617F	hematologic cancer	resistant	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 R953*	hematologic cancer	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 R953* in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	sensitive	Midostaurin + Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited downstream signaling and cell growth in transformed hematologic cells expressing aa FLT3-ITD mutation and JAK3 V722I in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	resistant	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	resistant	Gilteritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Xospata (gilteritinib) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	decreased response	Pacritinib	Preclinical - Cell culture	Actionable	In a preclinical study, Vonjo (pacritinib) treatment decreased cell proliferation and Akt and Erk phosphorylation, but did not fully inhibit Stat5 phosphorylation in transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I and was less effective compared to treatment with the combination of a FLT3 inhibitor and a JAK inhibitor in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	resistant	Tofacitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Xeljanz (tofacitinib) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	sensitive	Midostaurin + Tofacitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Rydapt (midostaurin) and Xeljanz (tofacitinib) inhibited cell growth and downstream signaling of transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	resistant	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267).	33149267
FLT3 exon 14 ins JAK3 V722I	hematologic cancer	sensitive	Gilteritinib + Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Xospata (gilteritinib) and Jakafi (ruxolitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I in culture (PMID: 33149267).	33149267

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