Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736.

Abstract

Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.

• Authors: Andrew S Moore, Amir Faisal, Grace W Y Mak, Farideh Miraki-Moud, Vassilios Bavetsias, Melanie Valenti, Gary Box, Albert Hallsworth, Alexis de Haven Brandon, Cristina P R Xavier, Randal Stronge, Andrew D J Pearson, Julian Blagg, Florence I Raynaud, Rajesh Chopra, Suzanne A Eccles, David C Taussig, Spiros Linardopoulos
• Journal: Blood advances (Blood Adv) Vol. 4 Issue 7 Pg. 1478-1491 (04 14 2020) ISSN: 2473-9537 [Electronic] United States
• PMID: 32282883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Benzothiazoles
• Phenylurea Compounds
• Protein Kinase Inhibitors
• quizartinib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• Aurora Kinases

Topics

• Aurora Kinases
• Benzothiazoles
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• fms-Like Tyrosine Kinase 3 (genetics)