Reasearch Awards nomination

Email updates

Keep up to date with the latest news and content from Molecular Cancer and BioMed Central.

Open Access Highly Accessed Research

Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms

Kerstin Maria Kampa-Schittenhelm1*, Michael Charles Heinrich2, Figen Akmut1, Hartmut Döhner3, Konstanze Döhner3 and Marcus Matthias Schittenhelm1

Author Affiliations

1 Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, University Hospital Tübingen, Tübingen, Germany

2 Department of Medicine; Division of Hematology and Medical Oncology, Portland VA Medical Center and OHSU Knight Cancer Institute, Portland, OR, USA

3 Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany

For all author emails, please log on.

Molecular Cancer 2013, 12:19  doi:10.1186/1476-4598-12-19

Published: 7 March 2013

Abstract

Background

Activating mutations of class III receptor tyrosine kinases (RTK) FLT3, PDGFR and KIT are associated with multiple human neoplasms including hematologic malignancies, for example: systemic mast cell disorders (KIT), non-CML myeloproliferative neoplasms (PDGFR) and subsets of acute leukemias (FLT3 and KIT). First generation tyrosine kinase inhibitors (TKI) are rapidly being integrated into routine cancer care. However, the expanding spectrum of TK-mutations, bioavailability issues and the emerging problem of primary or secondary TKI-therapy resistance have lead to the search for novel second generation TKIs to improve target potency and to overcome resistant clones.

Quizartinib was recently demonstrated to be a selective FLT3 inhibitor with excellent pharmacokinetics and promising in vivo activity in a phase II study for FLT3 ITD + AML patients. In vitro kinase assays have suggested that in addition to FLT3, quizartinib also targets related class III RTK isoforms.

Methods

Various FLT3 or KIT leukemia cell lines and native blasts were used to determine the antiproliferative and proapoptotic efficacy of quizartinib. To better compare differences between the mutant kinase isoforms, we generated an isogenic BaF3 cell line expressing different FLT3, KIT or BCR/ABL isoforms. Using immunoblotting, we examined the effects of quizartinib on activation of mutant KIT or FLT3 isoforms.

Results

Kinase inhibition of (mutant) KIT, PDGFR and FLT3 isoforms by quizartinib leads to potent inhibition of cellular proliferation and induction of apoptosis in in vitro leukemia models as well as in native leukemia blasts treated ex vivo. However, the sensitivity patterns vary widely depending on the underlying (mutant)-kinase isoform, with some isoforms being relatively insensitive to this agent (e.g. FLT3 D835V and KIT codon D816 mutations). Evaluation of sensitivities in an isogenic cellular background confirms a direct association with the underlying mutant-TK isoform – which is further validated by immunoblotting experiments demonstrating kinase inhibition consistent with the cellular sensitivity/resistance to quizartinib.

Conclusion

Quizartinib is a potent second-generation class III receptor TK-inhibitor – but specific, mutation restricted spectrum of activity may require mutation screening prior to therapy.

Keywords:
AC220; Quizartinib; Leukemia; KIT; FLT3; PDGFR