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MELK-T1, a small molecule inhibitor of protein kinase MELK, decreases DNA damage tolerance in highly proliferating cancer cells

ABSTRACT: Maternal Embryonic Leucine Zipper Kinase (MELK), a Ser/Thr protein kinase, is highly over expressed in stem and cancer cells. The oncogenic role of MELK is attributed to its capacity to disable critical cell cycle checkpoints and to enhance replication. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing, but this is often compromised by off target effects. Here we present the cellular validation of a novel, potent and selective small molecule MELK inhibitor, MELK-T1, which has enabled us to explore the biological function of MELK. Strikingly, the binding of MELK-T1 to endogenous MELK triggers a rapid and proteasome dependent degradation of the MELK protein. Treatment of MCF-7 breast adenocarcinoma cells with MELK-T1 leads to an accumulation of stalled replication forks and double strand breaks, followed by a replicative senescence phenotype. This phenotype correlates with a rapid and long-lasting ATM activation and phosphorylation of CHK2. Furthermore, MELK-T1 induces strong phosphorylation of p53 and prolonged up-regulation of p21. Our data generated with MELK-T1 indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA damage tolerance. Thus, targeting MELK by combined inhibition of its catalytic function and inhibitor-induced degradation might sensitize tumors to DNA-damaging agents or radiation therapy, by lowering the DNA damage threshold.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62477 | GEO | 2015/12/11

SECONDARY ACCESSION(S): PRJNA264218

REPOSITORIES: GEO

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