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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

1
Department for Biomedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
2
Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
Cancers 2018, 10(6), 170; https://doi.org/10.3390/cancers10060170
Received: 13 April 2018 / Revised: 25 May 2018 / Accepted: 29 May 2018 / Published: 31 May 2018
(This article belongs to the Special Issue p53 Signaling in Cancers)
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. View Full-Text
Keywords: acute myeloid leukemia (AML); FMS like tyrosine kinase 3 (FLT3); tumor suppressor p53 (TP53); mouse double minute 2 homolog (MDM2); mitogen-activated protein kinase kinase (MEK; MAP2K; MAPKK) acute myeloid leukemia (AML); FMS like tyrosine kinase 3 (FLT3); tumor suppressor p53 (TP53); mouse double minute 2 homolog (MDM2); mitogen-activated protein kinase kinase (MEK; MAP2K; MAPKK)
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Seipel, K.; Marques, M.A.T.; Sidler, C.; Mueller, B.U.; Pabst, T. 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 2018, 10, 170.

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