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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.
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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, Nov 2023). 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 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
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