S100A8 and S100A9 Proteins in Tyrosine Kinase Inhibitor Resistance in FLT3‐ITD‐Positive Acute Myeloid Leukemia
Authors: Zavorka Thomas Megan E. , Buelow Daelynn R. , Jeon Jae Yoon , Pounds Stanley B. , Baker Sharyn D. 
Published: June 2021

Despite advances made recently in developing targeted therapies for acute myeloid leukemia (AML), long‐term overall survival is poor in adults and certain subtypes of pediatric AML. FLT3 receptor tyrosine kinase (TK) with internal tandem duplications (ITD) is a subset of AML with frequent relapse, and small molecule TK inhibitors (TKIs) against FLT3 are currently in clinical trials. However, many patients develop resistance to these agents, mainly via secondary mutations in the TK domain (TKD) of FLT3, but additional mechanisms of acquired resistance and factors involved in intrinsic resistance are largely unknown. There is a great need to understand these underlying mechanisms of TKI resistance in order to develop combination chemotherapy to produce durable responses and prolong survival.

The calcium‐binding proteins, S100A8 and S100A9, have been linked to inflammation and cancer, and their expression correlates with poorer prognosis. These proteins bind intracellular calcium, but can be secreted and act within the microenvironment to promote cell cycle progression and differentiation processes. Recently, these proteins have been detected in the serum of AML patients and mouse models of AML, implicating a role in this disease. We hypothesize that TKI therapy upregulates S100A8 and S100A9, circumventing the anti‐leukemic activity of drug treatment.

In our preliminary studies, mice with FLT3‐ITD+ AML treated with a type II (sorafenib) FLT3 inhibitor developed eventual resistance through TKD mutations, determined via deep amplicon sequencing of bone marrow resistant cells, while mice treated in combination with sorafenib and a type I (crenolanib) FLT3 inhibitor had a significantly lower TKD mutational burden (t‐test FDR, q<0.05), yet developed eventual resistance. Microarray gene expression analysis on blast samples determined the differentially expressed genes between mice treated with vehicle, or sorafenib alone or in combination with crenolanib. S100A8 and S100A9 were two of the top genes that were differentially upregulated in the treatment group with low TKD mutation burden versus the other treatment groups. These data were confirmed by RT‐PCR, in which the highest expression of S100A8/A9 was observed in the TKI combination group with low TKD mutation burden versus sorafenib and vehicle groups. Furthermore, two human FLT3‐ITD+ AML cell lines treated with these TKIs showed an acute upregulation of S100A8 and S100A9. We have shown that S100A8/A9 are elevated during TKI treatment, especially with a type I TKI regimen. Thus, our data support the premise that these S100s may contribute to a novel mechanism of intrinsic and/or acquired TKI‐resistance, which can be further exploited to design better combinatorial chemotherapy approaches.

Support or Funding Information

This work is supported by the National Cancer Institute under award R01 CA138744‐08 and the Ohio State University Comprehensive Cancer Center Pelotonia Foundation.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.