The Cellular p53 Inhibitor MDM2 and the Growth Factor Receptor FLT3 as Biomarkers for Treatment Responses to the MDM2-Inhibitor Idasanutlin and the MEK1 Inhibitor Cobimetinib in Acute Myeloid Leukemia.

Seipel, Katja; Marques, Miguel A T; Sidler, Corinne; Mueller, Beatrice U; Pabst Müller, Thomas Niklaus (2018). The Cellular p53 Inhibitor MDM2 and the Growth Factor Receptor FLT3 as Biomarkers for Treatment Responses to the MDM2-Inhibitor Idasanutlin and the MEK1 Inhibitor Cobimetinib in Acute Myeloid Leukemia. Cancers, 10(6) MDPI AG 10.3390/cancers10060170

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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 and 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 and elevated FLT3 and MDM2 protein levels. Our data indicate that AML cells with normal karyotype (NK) and wild-type status of 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.

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