title: Abrogation of the G2 checkpoint by inhibition of Wee-1 kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents.
abstract: Inducing DNA damage is a well known strategy for attacking cancer, already being used for many years by the application of a variety of anti cancer drugs. Tumor cells and other rapidly dividing cells are more sensitive to DNA damage caused by DNA damaging agents compared to normal cells. While normal cells can rely on various mechanisms for DNA repair in order to protect the integrity of the genome and to promote cell survival, most tumor cells, due to genetic changes, are more challenged when it comes to repair of DNA damage. Wee 1 is a tyrosine kinase that phosphorylates CDC2 at Tyr 15 and as such plays a pivotal role in the G2 DNA damage checkpoint. The strategy of inhibition of Wee 1 by a tyrosine kinase inhibitor is exploiting the impaired options for DNA damage repair especially in cells with deregulated p53, which results in malfunction of the G1 checkpoint. Tumor cells that are unable to rely on the G1 checkpoint are more sensitive to G2 checkpoint abrogation. Administration of DNA damaging chemotherapy in combination with a Wee 1 inhibitor may therefore selectively sensitize p53 deficient cells, while normal cells are spared from toxicity. PD-166285 has been described as a novel G2 abrogator and Wee 1 inhibitor, but has also been characterized as a broad-spectrum receptor tyrosine kinase inhibitor. MK-1775 is a specific and potent inhibitor of Wee-1 and is currently under investigation in a multi-center phase I study in combination with either gemcitabine, carboplatin or cisplatin in patients with advanced solid tumors. Preliminary results show good tolerability and promising anti-cancer activity.
authors.affiliation: Department of Experimental Therapy, The Netherlands Caner Institute, Amsterdam, The Netherlands. j.schellens@nki.nl
authors.forename: Suzanne
authors.initials: S
authors.lastname: Leijen
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C109647:PD 166285; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib