New tyrosine kinase inhibitor shows promise
MRX-2843 is a tyrosine kinase inhibitor that targets the receptor tyrosine kinases MERTK and FLT3. Both MERTK and FLT3 are promising targets in acute myeloid leukemia (AML). MERTK is overexpressed in over 80% of AML cases, and internal tandem duplication (ITD) mutations of FLT3 (FLT3-ITD) are found in 20-30% of adults and 10-15% of children with AML.
FLT3 encodes FMS-like receptor tyrosine kinase-3. ITD mutations of FLT3 cause constitutive activation of the kinase and are associated with a poor prognosis in patients with AML. Numerous FLT3 inhibitors, such as quizartinib, are currently under investigation in clinical trials and patients initially respond well. However, resistance to the inhibitors can develop quickly, meaning that the duration of the response is short-lived. Therefore, it is important to explore compounds, such as MRX-2843, that target alternative tyrosine kinases.
MRX-2843 was shown to exert anti-tumor effects in culture and in preclinical models as reported by a group of researchers from the Aflac Cancer & Blood Disorders Center of Children’s Healthcare, Atlanta, GA, the University of North Carolina, Chapel Hill, NC and the University of California, San Francisco, CA.
MRX-2843 works by inhibiting the phosphorylation of MERTK and FLT3, and the activation of their downstream effectors. This leads to apoptosis and a decreased clonal expansion and/or colony formation in cell lines of AML and patient samples. Using a murine xenograft model in which patient-derived AML cells were injected, the group further found that daily oral MRX-2843 treatment improved survival. This was even the case for xenograft models with resistance to the FLT3 inhibitor quizartinib.
In light of the results of this preclinical characterization of MRX-2843, the group concludes that it is worth exploring the clinical utility of MRX-2843 for AML further.
Results are published in JCI insight.
- Minson K, Smith C, DeRyckere D, Libbrecht C, Lee-Sherick A, Huey M, et al. The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI Insight. 2016 Mar 1;1(3):e85630. PMID: 27158668
- Douglas G. Identification of a novel tyrosine kinase inhibitor for acute myeloid leukemia [Internet]. EurekaAlert. 2016. Available from: http://www.eurekalert.org/pub_releases/2016-03/joci-ioa031616.php