FLT3 INHIBITORS IN THE TREATMENT OF FLT3/ITD AML: OVERCOMING RESISTANCE AND DEFINING A THERAPEUTIC INDEX

AML;TKI;RESISTANCE;Biology

Galanis, Allison ElizabethBrown, Patrick A. ;

Johns Hopkins University

关键词: AML;    TKI;    RESISTANCE;    Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37956/GALANIS-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Mutations of the type III receptor tyrosine kinase (RTK) FLT3 occur in approximately 30% of acute myeloid leukemia (AML) patients and lead to constitutive activation.This has made FLT3 activating mutations an attractive drug target, as 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 as well as against 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 to other available FLT3 TKIs such as quizartinib and sorafenib.Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared to 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 AML 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.Several small molecule tyrosine kinase inhibitors (TKIs) used to treat hematologic malignancies have off target effects against c-Kit, a receptor tyrosine kinase required for normal hematopoiesis.In animal models, abnormal c-Kit signaling results in impaired erythroid and megakaryocyte production.AML patients taking FLT3 inhibitors with activity against c-Kit experience myelosuppression.To investigate the relationship between c-Kit inhibition and myelosuppression, a panel of FLT3, c-Kit, and dual inhibitors were investigated.The activity of each drug was determined against FLT3 and c-Kit and on hematopoietic colony formation.Potent c-Kit inhibitors such as dasatinib, pazopanib, and quizartinib demonstrated the greatest disruption of erythroid colony formation.Sorafenib, which has negligible activity against c-Kit, demonstrated minimal disruption of normal colony formation.Our data highlights the importance of determining a therapeutic index between the targeted receptor and c-KIT for TKIs used to treat hematologic malignancies in order to maintain normal hematopoiesis and improve overall treatment outcomes.