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

  • Biosci Rep. 2015 Oct 2;35(6):e00267. doi: 10.1042/BSR20150194.
Lijs Beke  1 ,  Cenk Kig  2 ,  Joannes T M Linders  1 ,  Shannah Boens  2 ,  An Boeckx  1 ,  Erika van Heerde  1 ,  Marc Parade  1 ,  An De Bondt  3 ,  Ilse Van den Wyngaert  3 ,  Tarig Bashir  1 ,  Souichi Ogata  1 ,  Lieven Meerpoel  1 ,  Aleyde Van Eynde  2 ,  Christopher N Johnson  4 ,  Monique Beullens  5 ,  Dirk Brehmer  6 ,  Mathieu Bollen  5
Affiliations
  • 1. Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 2. Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium.
  • 3. Computational Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 4. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • 5. Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium [email protected] [email protected] [email protected].
  • 6. Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium [email protected] [email protected] [email protected].
PMID: 26431963 DOI: 10.1042/BSR20150194
Abstract

Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many Cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (Chk2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold.

Keywords
chemical biology; deoxyribonucleic acid (DNA) damage response; maternal embryonic leucine zipper kinase (MELK) kinase; senescence; small molecule inhibitors.
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