Preclinical research indicates that a novel inhibitor can overcome resistance-conferring FLT3 mutations in acute myeloid leukemia (AML).
The MERTK/FLT3 inhibitor MRX-2843 induced apoptosis and inhibited colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD.
MRX-2843 also improved survival in mouse models of AML, including cases where tumors were resistant to the FLT3 inhibitor quizartinib.
Douglas Graham, MD, PhD, of the University of Colorado in Aurora, and his colleagues conducted this research and reported the results in JCI Insight.
The researchers previously showed that the receptor tyrosine kinase MERTK is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis.
With the current study, they showed that MRX-2843 abrogates activation of MERTK, FLT3, and their downstream effectors. And this translates to antileukemic activity in vitro and in vivo.
MRX-2843 inhibited MERTK signaling, induced cell death, and abolished oncogenic phenotypes in AML cells. The drug also exhibited therapeutic activity in a MERTK-dependent xenograft model.
MRX-2843 was able to stop the activation of FLT3 and its signaling pathways almost completely. The researchers said this suggests the drug has somewhat higher cellular potency against FLT3 relative to MERTK.
In mouse models of FLT3-ITD AML, MRX-2843 significantly prolonged survival when compared to vehicle control.
The researchers also said MRX-2843 selectively inhibited colony formation in primary AML patient samples. Primary human MERTK-expressing leukemic blasts, with or without FLT3-ITD mutations, proved sensitive to treatment with MRX-2843.
In addition, MRX-2843 increased survival and decreased peripheral disease burden in patient-derived xenograft models of AML—both MERTK+FLT3-WT and MERTK+FLT3-ITD models.
Finally, the researchers found that MRX-2843 was active against quizartinib-resistant FLT3-mutant proteins, induced apoptosis and inhibited colony formation in quizartinib-resistant FLT3-ITD cell lines, and prolonged survival in quizartinib-resistant FLT3-ITD xenograft models.
