A novel in-vitro model of the bone marrow microenvironment in AML identifies CD44 and Focal Adhesion Kinase as therapeutic targets to reverse cell adhesion-mediated drug resistance

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Abstract Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, disruption of the BMME, releasing tumour cells into the peripheral circulation, has therapeutic potential. Using both primary donor AML cells and cell lines, we developed an in-vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistanc E. We identified anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signalling as a contributing factor; adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing adhesion of the most primitive CD34 high AML cells in primary autologous co-cultures. Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanised monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.

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