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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 Nature communications
Vol 10
Issue 1
Date 2019 01 16
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 and therefore, is predicted to have no effect on Flt3 protein function (PMID: 30651561).
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 and therefore, is predicted to have no effect on Flt3 protein function (PMID: 30651561). 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 compared to wild-type Flt3 (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 and therefore, is predicted to have no effect on Flt3 protein function (PMID: 30651561).
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 D835Y IDH1 wild-type hematologic cancer sensitive AGI-5198 + Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, in combination with AGI-5198, synergistically decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Idh1 wild-type (PMID: 30651561). 30651561
FLT3 K429E hematologic cancer resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib did not decrease cell proliferation of transformed mouse cells expressing Flt3 K429E (PMID: 30651561). 30651561
FLT3 D835Y IDH1 wild-type hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Idh1 wild-type (PMID: 30651561). 30651561
FLT3 D835Y IDH1 R132H hematologic cancer resistant AGI-5198 Preclinical - Cell culture Actionable In a preclinical study, AGI-5198, did not decrease cell proliferation of transformed mouse cells expressing Flt3 D835Y and Idh1 R132H (PMID: 30651561). 30651561
FLT3 D835Y IDH1 R132H hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Idh1 R132H (PMID: 30651561). 30651561
FLT3 D200N FLT3 D835Y hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Flt3 D200N (PMID: 30651561). 30651561
FLT3 D835Y PTPN11 A72D hematologic cancer sensitive Crenolanib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, in combination with Mekinist (trametinib), synergistically decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Ptpn11 A72D (PMID: 30651561). 30651561
FLT3 F691L FLT3 D835Y hematologic cancer resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib did not decrease cell proliferation of transformed mouse cells expressing Flt3 D835Y and Flt3 F691L, indicating F691L as a resistance mutation since D835Y was sensitive alone (PMID: 30651561). 30651561
FLT3 D835Y PTPN11 A72D hematologic cancer resistant Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, did not decrease cell proliferation of transformed mouse cells expressing Flt3 D835Y and Ptpn11 A72D, indicating Ptpn11 A72D as a resistance mutation since Flt3 D835Y was sensitive alone (PMID: 30651561). 30651561
FLT3 D835Y IDH1 wild-type hematologic cancer resistant AGI-5198 Preclinical - Cell culture Actionable In a preclinical study, AGI-5198, did not decrease cell proliferation of transformed mouse cells expressing Flt3 D835Y and Idh1 wild-type (PMID: 30651561). 30651561
FLT3 D835Y hematologic cancer sensitive Crenolanib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, in combination with Mekinist (trametinib), synergistically decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y (PMID: 30651561). 30651561
FLT3 L601F FLT3 D835Y hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Flt3 L601F (PMID: 30651561). 30651561
FLT3 D835Y hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib decreased cell proliferation of transformed mouse cells expressing FLT3 D835Y (PMID: 30651561). 30651561
FLT3 Y572C hematologic cancer sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib decreased cell proliferation of transformed mouse cells expressing Flt3 Y572C (PMID: 30651561). 30651561
FLT3 D835Y IDH1 R132H hematologic cancer sensitive AGI-5198 + Crenolanib Preclinical - Cell culture Actionable In a preclinical study, Crenolanib, in combination with AGI-5198, synergistically decreased cell proliferation of transformed mouse cells expressing Flt3 D835Y and Idh1 R132H (PMID: 30651561). 30651561