WEE1 controls CDK1 and CDK2 activity during S phase, thereby suppressing excessive firing of replication origins, promoting homologous recombination, and preventing excessive resection of stalled replication forks Beck et al. Figure 2.
WEE1 inhibitors have been developed, and some have entered into clinical trials but clinical data are still limited. The pyeazolo-pyrimidine derivative MK is the most potent and highly selective inhibitor of Wee1, and has recently reached phase I in combination with gemcitabine, cisplatin, or carboplatin and II studies in combination with paclitaxel and carboplatin in ovarian cancer Stathis and Oza, ; De Witt Hamer et al.
Most research has focused on the development of CHK1 inhibitors, which have entered clinical studies. UCN 01 was the first of this type of inhibitor to enter clinical trials, but after Phase II trials it was discontinued owing to dose-limiting toxicities and a lack of convincing efficacy that was probably due to poor specificity and pharmacokinetics. The newer, more specific inhibitors of CHK1 have generally been combined with gemcitabine in Phase I studies, in which myelosuppression was the major toxicity that led to the termination of the trials, and no efficacy data have yet been presented Carrassa and Damia, ; Blasina et al.
Recently, a selective orally available inhibitor developed from a high-throughput screening hit, GNE, gave promising pre-clinical studies and is now undergoing Phase I clinical trials Blackwood et al. The most promising prospect for the future of cancer treatment seems to be the exploitation of dysregulated DNA Damage Response, by the synthetic lethality approach.
The synthetic lethality concept states that mutations of two different genes are not lethal in the cells when they occur at once, but are synthetically lethal, causing cells to die, if they occur simultaneously. Synthetic lethal interactions have been widely reported for loss and gain of function mutations. The synthetic lethality-driven approach offers the ideal cancer therapy as it allows indirect targeting of non-druggable cancer-promoting lesions with pharmacological inhibition of the druggable synthetic lethal interactor and as it should be exclusively selective for cancer cells, and well tolerated by healthy normal cells, that lack the cancer-specific mutation, with a wide therapeutic window Kaelin Jr, ; Canaani, Chk1 inhibition has been proposed as a strategy for targeting FA Fanconi Anemia pathway deficient tumors.
In fact, tumor cells deficient in the FA pathway are hypersensitive to Chk1 inhibition, suggesting a possible use of these inhibitors in FA deficient tumors Chen et al. A range of sporadic tumors with genetic and epigenetic disruption of the FA genes have been reported. Hyperactive growth factor signalling and oncogene-induced replicative stress increase DNA breakage that activates the ATR-CHK1 pathway, and some examples of the synthetic lethality of checkpoint or DNA repair inhibitors in cells harbouring activated oncogenes have been identified.
Many recent studies with a high throughput siRNA screening approach led to identification of other possible target genes synthetically lethal with Chk1 inhibitors. Recently two distinct siRNA high-throughput screening identified Wee1 as in synthetic lethality with Chk1 Davies et al.
The strong in vitro synergistic effect of the combination translates to tumor growth inhibition in vivo Carrassa et al.
Cell-cycle checkpoints and cancer | Nature
Simultaneous inhibition of CHK1 and WEE1 induces cell death through a general mis-coordination of the cell cycle figure 3 , which leads to DNA damage and collapsed replication forks during S phase Carrassa et al. These data have been recently corroborated by other groups, suggesting that at least in solid tumors this drug combination could be a very new promising anticancer strategy deserving clinical investigation Russell et al. Many other successful synthetic lethality combinations exist and many more probably need to be explored and they will provide in the near future new potential effective tools for cancer therapy Reinhardt et al.
Bibliography Principles of CDK regulation. Morgan DO. Genes Dev. Pavletich NP. J Mol Biol.
Epub Oct Cell Prolif. Cell Cycle. Epub Sep Kastan MB, Bartek J. Massague J. Cobrinik D. Gottifredi V, Prives C. Semin Cell Dev Biol. Kaelin WG Jr. Nat Rev Cancer. Mol Cell Biol. Nat Cell Biol. Epub Dec 4.
Bartek J, Lukas J. Curr Opin Cell Biol. Epub Feb Dev Cell. Mol Cancer Ther. Branzei D, Foiani M. Nat Rev Mol Cell Biol. Clin Cancer Res. Biochim Biophys Acta. Epub Apr Canaani D. Br J Cancer. Epub Mar J Cell Mol Med. Mol Cancer. N Engl J Med. Epub Jun J Cell Physiol.
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DNA Repair Amst. Epub May Dai Y, Grant S. PAM50 subtype calls were based on microarray gene expression data. Results were obtained from at least three independent experiments for each cell line. Cells were passaged approximately once a week and fed every 2—3 days with fresh medium. Standard immunoblotting techniques were used to detect phosphorylated and total proteins as previously described.
The Cell Cycle in Normal Cells
The increment of increase in protein levels for the drug-treated samples compared to DMSO samples were used to measure protein activation. Values were subsequently normalized to the increment measured for the same NHF1-hTERT positive control sample as an internal normalization control to facilitate comparisons among different western blots and account for different exposures. Western blots shown are representative of two independent experiments. All analyses were performed blinded to sample identity.
FISH samples were prepared as previously described. The severity of cohesion defects was assessed based on a previous study. Cell line gene expression data were obtained from Dr. Katherine Hoadley and Dr. Charles M. If the statistical conclusions were the same in both the primary and sensitivity analyses, it was concluded that the particular observation did not unduly influence the analysis and the primary analysis result was reported as statistically significant.
Bower, J. Topoisomerase IIalpha maintains genomic stability through decatenation G 2 checkpoint signaling. Taylor, S.
Kinetochore localization of murine bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89 , — Hartwell, L.