Reference Detail

Ref Type

Journal Article

PMID

(19318574)

Authors

von Bubnoff N, Engh RA, Aberg E, Sanger J, Peschel C, Duyster J

Title

FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	69	7	2009 Apr 1	3032-41	Cancer Res

URL

Abstract Text

FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelogenous leukemia (AML). Secondary mutations in target kinases can cause clinical resistance to therapeutic kinase inhibition. We have previously shown that sensitivity toward tyrosine kinase inhibitors varies between different activating FLT3 mutations. We therefore intended to determine whether different FLT3 inhibitors would produce distinct profiles of secondary, FLT3 resistance mutations. Using a cell-based screening approach, we generated FLT3-internal tandem duplication (ITD)-expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. Interestingly, the profile of resistance mutations emerging with SU5614 was limited to exchanges in the second part of the kinase domain (TK2) with exchanges of D835 predominating. In contrast, PKC412 exclusively produced mutations within tyrosine kinase domain 1 (TK1) at position N676. A mutation at N676 recently has been reported in a case of PKC412-resistant AML. TK1 mutations exhibited a differential response to SU5614, sorafenib, and sunitinib but strongly impaired response to PKC412. TK2 exchanges identified with SU5614 were sensitive to PKC412, sunitinib, or sorafenib, with the exception of Y842D, which caused a strong resistance to sorafenib. Of note, sorafenib also produced a highly distinct profile of resistance mutations with no overlap to SU5614 or PKC412, including F691L in TK1 and exchanges at position Y842 of TK2. Thus, different FLT3 kinase inhibitors generate distinct, nonoverlapping resistance profiles. This is in contrast to Bcr-Abl kinase inhibitors such as imatinib, nilotinib, and dasatinib, which display overlapping resistance profiles. Therefore, combinations of FLT3 inhibitors may be useful to prevent FLT3 resistance mutations in the setting of FLT3-ITD-positive AML.

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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
FLT3	F691L	missense	no effect - predicted	FLT3 F691L lies within the protein kinase domain of the Flt3 protein (PMID: 23430109). F691L has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 23430109, PMID: 19318574, PMID: 22504184, PMID: 29187377), but is not transforming in cell culture (PMID: 30651561), and therefore, is predicted to have no effect on Flt3 protein function.	Y
FLT3	M855T	missense	unknown	FLT3 M855T lies within the protein kinase domain of the Flt3 protein (UniProt.org). M855T has been identified in the scientific literature (PMID: 32040554, PMID: 19318574), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Jan 2024).
FLT3	Y842D	missense	unknown	FLT3 Y842D lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y842D has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 19318574, PMID: 25487917), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 Y842D	hematologic cancer	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) inhibited proliferation of transformed hematologic cells expressing FLT3-ITD with FLT3 Y842D in culture (PMID: 19318574).	19318574
FLT3 exon 14 ins FLT3 Y842D	hematologic cancer	sensitive	Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed hematologic cells expressing FLT3-ITD with FLT3 Y842D in culture (PMID: 19318574).	19318574
FLT3 exon 14 ins FLT3 Y842D	hematologic cancer	resistant	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed hematologic cells expressing FLT3-ITD with FLT3 Y842D were resistant to Nexavar (sorafenib) treatment in culture (PMID: 19318574).	19318574