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Abstract
The tumor suppressor protein p53 is inactivated in a large variety of cancer cells. Cellular p53 inhibitors like the mouse double minute 2 homolog (MDM2) commonly suppress the p53 function in acute myeloid leukemia (AML). Moreover, fms like tyrosine kinase 3 (FLT3) growth factor signaling pathways including the mitogen-activated kinase (MAPK) cascade (RAS-RAF-MEK-ERK) are highly active in AML cells. Consequently, the combined administration of MDM2 and MEK inhibitors may present a promising anti-leukemic treatment strategy. Here we assessed the MDM2 antagonist idasanutlin and the MEK1 inhibitor cobimetinib as single agents and in combination in a variety of AML cell lines and primary AML blast cells for their ability to induce apoptosis and cell death. AML cell lines and blast cells comprised all major AML subtypes based on the mutational status of TP53, FLT3 and NPM1 genes. We observed a considerably varying anti-leukemic efficacy of idasanutlin and cobimetinib. AML cells with high sensitivity to the single compounds as well as to the combined treatment emerged with normal karyotype, wild-type TP53 and elevated FLT3 and MDM2 protein levels. Our data indicate that AML cells with normal karyotype (NK) and wild-type status of TP53 with elevated FLT3 and MDM2 expression emerge to be most sensitive to the combined treatment with cobimetinib and idasanutlin. FLT3 and MDM2 are biomarkers for treatment response to idasanutlin and cobimetinib in AML.
Highlights
Based on its fundamental role in induction of cell cycle arrest and apoptosis there is tight regulation of the function of the tumor suppressor p53 in normal cells
In acute myeloid leukemia (AML), the p53 function is rarely disrupted by tumor suppressor p53 (TP53) gene mutations, but more often by dysregulation of the nucleolar phosphoprotein nucleophosmin (NPM1) [1], the cellular p53 inhibitor
AML subtypes characterized by the fms like tyrosine kinase 3 (FLT3)-ITD and FLT3 wild type, NPM1 mutant and wild type, TP53 mutant and wild type as well as RAS mutant and wild type genes (Table 1)
Summary
Based on its fundamental role in induction of cell cycle arrest and apoptosis there is tight regulation of the function of the tumor suppressor p53 in normal cells. The p53 function is frequently inactivated enabling evasion of growth control and outgrowth of malignant cells. In acute myeloid leukemia (AML), the p53 function is rarely disrupted by TP53 gene mutations, but more often by dysregulation of the nucleolar phosphoprotein nucleophosmin (NPM1) [1], the cellular p53 inhibitor. While the NPM1 gene is commonly mutated in AML, the protein levels of MDM2, Cancers 2018, 10, 170; doi:10.3390/cancers10060170 www.mdpi.com/journal/cancers. XPO1 and CUL9 are frequently elevated in AML cells [5]. In addition to p53 inactivation, there may be activation of oncogenes in the leukemic cell. A key oncogene in AML is the FMS-kinase 3 (FLT3) gene
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