Identifying Mechanisms of Resistance to Pharmacological Inhibition of the MLL-MENIN Interaction in Acute Myeloid Leukemia.

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Patients with Akute Myeloid Leukemia (AML) harboring translocations involving the MLL1-gene have adverse clinical outcomes despite aggressive treatment approaches like high-dose chemotherapy and allogenic stem cell transplantation. The oncogenic gene-fusion complex is driving transcriptional activation of a set of target genes that promote development and maintenance of AML in both adult and pediatric patients. Disrupting the function of this complex by genetic inactivation of specific members of this complex led to a block in disease progression and ultimately to a cure of AML in several preclinical animal models. Recently, the group of Prof. Scott Armstrong at Dana-Farber Cancer Institute in Boston has established a small-molecule drug, VTP50469, that disrupts the protein-protein interaction between the MLL-fusion oncogenes and MEN1, another crucial member of the aberrant transcriptional activator complex. VTP50469 is orally bioavailable and led to dramatic and long lasting responses in patient-derived Xenografts and will enter early-phase clinical trials in Summer 2019 in the United States. Nevertheless, preliminary experiments from Prof. Armstrong’s laboratory showed, that leukemia cells are able to adapt to treatment with the MEN1-Inhibitor in vitro leading to a resistant cell population that is able to proliferate despite presence of the drug. These cells lost their dependency on MEN1 as confirmed by CRISPR-Cas9 mediated knockout. During the course of the proposed project we aim to characterize changes in gene-expression and chromatin-state in VTP50469 resistant AML cell lines on a global scale. Subsequently, we plan to validate those findings in vivo using patient derived xenograft mouse-models. Furthermore, we will use a genome-wide CRISPR-Cas9 screening approach to identify specific genetic vulnerabilities in the MEN1-inhibitor resistant cells with the ultimate aim of identifying drug targets that could facilitate elimination of the resistant cell clone. Secondary drug resistance is a major clinical challenge particularly in targeted therapy approaches involving small molecule drugs. The preliminary data from the Armstrong-Laboratory promote the hypothesis that the medical community will have to deal with this issue in clinical management of VTP50469 and other MEN1-targeting drugs. With the proposed project we hope to provide first insights into the underlying mechanisms and potential strategies to overcome MEN1-inhibitor resistance.