Reference Detail

Ref Type

Journal Article

PMID

(24227820)

Authors

Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M

Title

Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	123	1	2014 Jan 2	94-100	Blood

URL

Abstract Text

Mutations of the type III receptor tyrosine kinase FLT3 occur in approximately 30% of acute myeloid leukemia patients and lead to constitutive activation. This has made FLT3-activating mutations an attractive drug target because they are probable driver mutations of this disease. As more potent FLT3 inhibitors are developed, a predictable development of resistance-conferring point mutations, commonly at residue D835, has been observed. Crenolanib is a highly selective and potent FLT3 tyrosine kinase inhibitor (TKI) with activity against the internal tandem duplication (FLT3/ITD) mutants and the FLT3/D835 point mutants. We tested crenolanib against a panel of D835 mutant cell lines and primary patient blasts and observed superior cytotoxic effects when compared with other available FLT3 TKIs such as quizartinib and sorafenib. Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. In progenitor cell assays, crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than quizartinib. Finally, correlative data from an ongoing clinical trial demonstrate that acute myeloid leukemia patients can achieve sufficient levels of crenolanib to inhibit both FLT3/ITD and resistance-conferring FLT3/D835 mutants in vivo. Crenolanib is thus an important next-generation FLT3 TKI.

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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
Crenolanib	Crenolanib	76	6

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Crenolanib		CP-868596\|CP-868,596	FLT3 Inhibitor 65 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
FLT3	D835F	missense	unknown	FLT3 D835F lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835F has been associated with FLT3 inhibitor resistance (PMID: 24227820, PMID: 23430109), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Oct 2023).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 D835F	acute myeloid leukemia	predicted - resistant	Sorafenib	Case Reports/Case Series	Actionable	In a clinical case study, FLT3 D835F was identified as an acquired resistance mutation in a patient with acute myeloid leukemia harboring a FLT3 internal tandem duplication (ITD) whose disease progressed on Nexavar (sorafenib) after initial response (PMID: 24227820).	24227820
FLT3 exon 14 ins FLT3 D835F	acute myeloid leukemia	predicted - sensitive	Crenolanib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Crenolanib inhibited growth of blasts derived from a patient with acute myeloid leukemia harboring FLT3 internal tandem duplication (ITD) and FLT3 D835F (PMID: 24227820).	24227820