Investigating the relationship between PI3K/AKT signalling and cell cycle checkpoints for cancer drug development
Supervisor(s): Dr Michelle Garrett
Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)
Team: Cell Cycle Control
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Summary
The PI3 Kinase (PI3K) signalling network plays a key role in the regulation of a number of cellular processes including cell growth, metabolism and survival and is a major target of deregulation in cancer [1]. This occurs through a number of mechanisms, including mutation of PI3K itself, loss of the lipid phosphatase PTEN and mutation of the serine/threonine kinase PKB/AKT. This strong relationship with cancer has led to PI3K signalling becoming an important focus of novel cancer drug development [1].
PI3K signalling may also play an important role in cell cycle checkpoint regulation by impairing the function of the cell cycle checkpoint kinase CHK1. CHK1 is activated in response to DNA damage, which causes cells to undergo cell cycle arrest at specific checkpoints, facilitating either DNA repair or cell death. Upregulated PI3K signalling has been reported to cause AKT-mediated Ser280 phosphorylation and cytoplasmic sequestration of CHK1, thus impairing its nuclear function [2]. The Centre for Cancer Therapeutics has been involved in the discovery and development of both PI3K signalling and CHK1 inhibitors as novel treatments for cancer [3,4]. The aim of the project is therefore to ask: “Is the PI3K network a major regulator of cell cycle checkpoint signalling in human cancer cells and can this relationship be exploited therapeutically?”
The first project aim will be to examine whether a relationship exists between PI3K signalling and CHK1 function in human tumour cell lines. A panel of human cell lines of defined PI3K, PTEN and AKT status and comprising examples of breast, colon, glioma and ovarian cancer will be used to determine whether there is a relationship between PI3K signalling, Ser280 CHK1 phosphorylation, CHK1 localisation and checkpoint activation? A complementary strategy for examining this relationship will be to select appropriate cell lines from the panel described above and to engineer deregulation of PI3K signalling in these cells. This will be done through either (i) knockdown of PTEN expression or (ii) overexpression of AKT, initially using transient methods and then by establishing stable cell lines. The effect of deregulated PI3K signalling on CHK1 regulation and checkpoint response will then be examined.
References
- Yap, T.A., et al. (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol Vol 8, No 4, p393-412
- Puc, J, et al. (2005) PTEN loss inhibits CHK1 to cause double stranded-DNA breaks in cells. Cancer Cell Vol 4, No 7, p193-204
- Caldwell, J.J., et al. (2008) Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration. J Med Chem Vol 51, No 7, p2147-2157
- Matthews, T.P., et al. (2009) Identification of inhibitors of checkpoint kinase 1 through template screening J Med Chem Vol 52, No 15, p4810-4819
