Dasatinib as a therapy for AML

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Exploring the potential of high-throughput drug testing with patient-derived AML cells is a powerful approach for discovering novel opportunities for patient treatment, drug repositioning, and new drug efficacies. We performed high-throughput drug sensitivity and resistance testing (DSRT) as well as genomic and transcriptomic profiling for 45 primary AML patient samples and 28 AML cell lines. Our key finding is that the combination of functional and molecular profiling suggests that;

"KIT pathway up-regulation + ex vivo efficacy = dasatinib treatment response in AML patients".

This study was done as part of the functional precision medicine program for leukemia patients, a joint effort between the Institute for Molecular Medicine Finland (FIMM) and the Helsinki University Hospital started in 2011. The AML patient specimens underwent molecular profiling and high-throughput drug testing, and the combined results were considered for real-time treatment decision making. The drug testing was performed with a large oncology compound collection (n=530) consisting of both approved and emerging small molecule drugs. The AML patient samples were freshly isolated from bone marrow samples making the drug response more representative of the patient situation as compared to bio-banked frozen material or established cell lines.

One of the most common efficacies seen across 290 drugs across 45 AML samples was dasatinib, which is a well-known multi-kinase inhibitor targeting KIT and other kinases and is commonly applied cancer drug. However, dasatinib is not formally indicated for AML treatment, even though there are previous reports that it can occasionally show efficacy in the patients. We first explored mutations as possible predictors of drug efficacy ex vivo but found no mutations that explained the efficacy of dasatinib. We then investigated the potential of gene expression profiles for predicting response to all the 290 drugs in the library, with a focus on dasatinib. We explored gene expression, not only one gene-at-a-time but also at the level of cell signaling pathways. The KIT pathway activation was informative of the dasatinib response but was not alone sufficient to predict its efficacy, likely due to the heterogeneous biology of AML. Therefore, we utilized ex vivo drug sensitivity information for bringing precision in predicting dasatinib response. The combination of ex vivo drug sensitivity for dasatinib and the KIT pathway activation turned out to be the best predictor of dasatinib response in AML.

This study has two implications. First, the combination of ex vivo drug efficacy testing and in vivo molecular profiling is highly informative in systematically predicting the efficacy of drugs. Second, clinical studies are warranted to formally establish the value dasatinib in treating those patients who have a KIT pathway up-regulation and who show dasatinib drug response ex vivo.

Disha Malani

Researcher, Institute for Molecular Medicine Finland (FIMM), University of Helsinki

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