Reference Detail

Ref Type

Journal Article

PMID

(25487917)

Authors

Li C, Liu L, Liang L, Xia Z, Li Z, Wang X, McGee LR, Newhall K, Sinclair A, Kamb A, Wickramasinghe D, Dai K

Title

AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	2	2015 Feb	375-83	Mol Cancer Ther

URL

Abstract Text

Resistance to FLT3 inhibitors is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG 925, a dual FLT3/CDK4 inhibitor, has been developed to overcome this resistance. It is hypothesized that the combined inhibition of FLT3 and CDK4 may reduce occurrence of the FLT3 resistance mutations, and thereby prolong clinical responses. To test this hypothesis, we attempted to isolate AML cell clones resistant to AMG 925 or to FLT3 inhibitors. After a selection of over 8 months with AMG 925, we could only isolate partially resistant clones. No new mutations in FLT3 were found, but a 2- to 3-fold increase in total FLT3 protein was detected and believed to contribute to the partial resistance. In contrast, selection with the FLT3 inhibitors sorafenib or AC220 (Quizartinib), led to a resistance and the appearance of a number of mutations in FLT3 kinase domains, including the known hot spot sites D835 and F691. However, when AC220 was combined with the CDK4 inhibitor PD0332991 (palbociclib) at 0.1 μmol/L or higher, no resistance mutations were obtained, indicating that the CDK4-inhibiting activity of AMG 925 contributed to the failure to develop drug resistance. AMG 925 was shown to potently inhibit the FLT3 inhibitor-resistant mutation D835Y/V. This feature of AMG 925 was also considered to contribute to the lack of resistance mutations to the compound. Together, our data suggest that AMG 925 has the potential to reduce resistance mutations in FLT3 and may prolong clinical responses.

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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	N841K	missense	unknown	FLT3 N841K lies within the activation loop of the protein kinase domain of the Flt3 protein (PMID: 25837374). N841K has been demonstrated to occur as a secondary resistance mutation in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 25847190, PMID: 25487917), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2024).	Y
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	resistant	Quizartinib	Preclinical - Cell culture	Actionable	In a preclinical study, FLT3 Y842D was identified as a secondary mutation in transformed hematologic cells expressing FLT3-ITD that acquired resistance to Vanflyta (quizartinib) in culture (PMID: 25487917).	25487917