Reference Detail

Ref Type

Journal Article

PMID

(30651561)

Authors

Zhang H, Savage S, Schultz AR, Bottomly D, White L, Segerdell E, Wilmot B, McWeeney SK, Eide CA, Nechiporuk T, Carlos A, Henson R, Lin C, Searles R, Ho H, Lam YL, Sweat R, Follit C, Jain V, Lind E, Borthakur G, Garcia-Manero G, Ravandi F, Kantarjian HM, Cortes J, Collins R, Buelow DR, Baker SD, Druker BJ, Tyner JW

Title

Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature communications	10	1	2019 01 16	244	Nat Commun

URL

Abstract Text

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

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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	D200N	missense	no effect - predicted	FLT3 D200N lies within the extracellular domain of the Flt3 protein (UniProt.org). D200N is not transforming in cell culture (PMID: 30651561), and therefore, is predicted to have no effect on Flt3 protein function.
FLT3	D835Y	missense	gain of function	FLT3 D835Y lies within the protein kinase domain activation loop of the Flt3 protein (UniProt.org, PMID: 11290608). D835Y results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420, PMID: 30651561), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).	Y
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	K429E	missense	gain of function - predicted	FLT3 K429E lies within the extracellular domain of the Flt3 protein (UniProt.org). K429E is predicted to confer a gain of function to the Flt3 protein, as demonstrated by transformation of cells in culture (PMID: 30651561).	Y
FLT3	L601F	missense	no effect - predicted	FLT3 L601F lies within the cytoplasmic domain of the Flt3 protein (UniProt.org). L601F is not transforming in cell culture (PMID: 30651561), and therefore, is predicted to have no effect on Flt3 protein function.
FLT3	Y572C	missense	gain of function	FLT3 Y572C lies within the cytoplasmic domain of the Flt3 protein (UniProt.org). Y572C results in constitutive phosphorylation of Flt3, activation of Erk, Akt and Stat signaling, and is transforming in cell culture (PMID: 18068628, PMID: 30651561).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins IDH1 R132H	hematologic cancer	sensitive	AGI-5198 + Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing FLT3-ITD and IDH1 R132H demonstrated increased sensitivity to treatment with the combination of Crenolanib (CP-868596) and AGI-5198 compared to treatment with Crenolanib (CP-868596) alone in culture (PMID: 30651561).	30651561
FLT3 D835Y IDH1 R132H	hematologic cancer	sensitive	AGI-5198 + Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Crenolanib (CP-868596) and AGI-5198 synergistically decreased proliferation of transformed cells expressing FLT3 D835Y and IDH1 R132H in culture (PMID: 30651561).	30651561
FLT3 D200N FLT3 D835Y	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3 D835Y and D200N in culture (PMID: 30651561).	30651561
FLT3 D835Y IDH1 wild-type	hematologic cancer	resistant	AGI-5198	Preclinical - Cell culture	Actionable	In a preclinical study, AGI-5198 treatment did not decrease proliferation of transformed cells expressing FLT3 D835Y and IDH1 wild-type in culture (PMID: 30651561).	30651561
FLT3 D835Y	hematologic cancer	sensitive	Crenolanib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Crenolanib (CP-868596) and Mekinist (trametinib) synergistically decreased proliferation of transformed cells expressing FLT3 D835Y in culture (PMID: 30651561).	30651561
FLT3 K429E	hematologic cancer	resistant	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) did not decrease proliferation of transformed cells expressing FLT3 K429E in culture (PMID: 30651561).	30651561
FLT3 L601F FLT3 D835Y	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3 D835Y and L601F in culture (PMID: 30651561).	30651561
FLT3 exon 14 ins IDH1 R132H	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3-ITD and IDH1 R132H in culture (PMID: 30651561).	30651561
FLT3 D835Y IDH1 R132H	hematologic cancer	resistant	AGI-5198	Preclinical - Cell culture	Actionable	In a preclinical study, AGI-5198 treatment did not decrease proliferation of transformed cells expressing FLT3 D835Y and IDH1 R132H in culture (PMID: 30651561).	30651561
FLT3 D835Y IDH1 R132H	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3 D835Y and IDH1 R132H in culture (PMID: 30651561).	30651561
FLT3 D835Y IDH1 wild-type	hematologic cancer	sensitive	AGI-5198 + Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Crenolanib (CP-868596) and AGI-5198 synergistically decreased proliferation of transformed cells expressing FLT3 D835Y and IDH1 wild-type in culture (PMID: 30651561).	30651561
FLT3 D835Y IDH1 wild-type	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3 D835Y and IDH1 wild-type (PMID: 30651561).	30651561
FLT3 F691L FLT3 D835Y	hematologic cancer	resistant	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) did not decrease proliferation of transformed cells expressing FLT3 D835Y and F691L in culture (PMID: 30651561).	30651561
FLT3 D835Y	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3 D835Y in culture (PMID: 30651561).	30651561
FLT3 Y572C	hematologic cancer	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, Crenolanib (CP-868596) decreased proliferation of transformed cells expressing FLT3 Y572C in culture (PMID: 30651561).	30651561