Abrogation of the G2 Checkpoint by Inhibition of Wee-1 Kinase Results in Sensitization of p53-Deficient Tumor Cells to DNA-Damaging Agents
Suzanne Leijen, Jos H. Beijnen and Jan H.M. Schellens
Affiliation: Department of Clinical Pharmacology and Pharmaceutical Sciences, Science Faculty Utrecht University, Utrecht The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Keywords: DNA damage, checkpoints, Wee1, inhibitor, phase I
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. Wee1 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 Wee1 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 Wee1 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 Wee1 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.
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