Phosphoinositide 3-kinases as drug targets in cancer
Introduction
Current views of cancer as the outcome of a multi-stage evolving genetic disease have been well described in recent reviews [1]. It is manifest as an increasing mass of cells, driven by proliferation, but potentially caused by the cells failing to die, and cell growth. The genetic aberrations that contribute to cancer progression produce their effects in a variety of ways. They can lead to upregulation of the activity of a gene, a potential oncogene, that favours survival, growth and/or proliferation. This can occur through changes in the sequence or size of a gene product as a result of somatic point mutations, translocations and/or increases in copy number (amplification). Indeed, activating somatic mutations (and somatic mutations without known effect), translocations and amplifications of PI3K (see Glossary) genes have been described in cancers. Several of the signalling targets of PI3Ks can also act as oncoproteins (e.g. PKB). Alternatively, genes that act as antagonists of the process of increasing cell mass — tumour suppressor genes — can, by mechanisms similar to those listed above, be lost. There are several tumour suppressor genes in the PI3K signalling web (e.g. PTEN, TSC1, TSC2, LKB 1 [which can carry germ-line familial mutations], Foxo1a, Foxo3a and possibly PHLPP; see Figure 1, Figure 2, Figure 3), most of which could render cancers insensitive to PI3K inhibitors (see below). The final class of mutations that can contribute to progression includes those in genes that influence genetic stability and hence the rate of mutation of tumour suppressors and oncogenes; they are not directly relevant here and will not be discussed.
Section snippets
The PI3K signalling web
The family of PI3Ks in mammalian cells can be divided into three classes (see Table 1). Type I PI3Ks are the best understood and are key players in a substantial intracellular signalling network, engaged by many growth and survival factors, which regulates cell proliferation, growth, survival and apoptosis [2]. The pattern of this regulation is hugely in favour of tumourigenesis; cell proliferation, growth and survival are enhanced and apoptosis is suppressed.
Type I PI3Ks integrate a wide
Cell responses dependent upon PI3K activity and relevant to tumour progression or treatment
It is possible to divide the cellular responses dependent on, or driven by, type I PI3K activity into various functional classes relevant to tumourigenesis or its treatment, even if the underpinning signalling pathways overlap or are not fully understood. However, none of the responses below are solely regulated by PI3K activity.
Specific roles for individual type I PI3Ks
All of the above could be seen as potentially beneficial, anti-tumour outcomes of inhibiting PI3K activity. However, the lack of selectivity of the reagents used in much of the above work means that the roles/importance of individual PI3Ks remains unclear.
Over the past few years, a steadily accumulating mass of data has begun to dissect the individual roles of PI3Ks. Murine knockouts of PI3Ks have shown that α and β subtypes are essential in early development and that δ, although not essential,
Consequences of mutations in PI3Kα
Three of the most common mutant versions (helical domain mutants E542K and E545K and the catalytic domain mutant H1047R) of PIK3CA in tumours have been expressed in chicken embryo fibroblasts [35••]. All three caused oncogenic transformation and led to constitutive increases in phosphorylation of PKB, S6K and 4E-bp1, whereas wild-type p110α had no effect. These important results demonstrate the somatic mutations are likely to contribute directly to tumour progression.
In vitro kinase assays with
PI3Kα as a target for chemotherapy
Clearly, the evidence discussed above represents a reasonable case for considering PI3Kα a potential target for chemotherapy; indeed, several companies have already accepted the evidence and are exploring this possibility. Although a variety of approaches could be considered, screening for small-molecule inhibitors of the catalytic ATP binding site appears to be the most practical. Interfering with activation of PI3Kα via its SH2 domains would be challenging and limited by the promiscuous use
What of the other PI3Ks?
None of the other PI3K catalytic subunits nor any of the PI3K-related protein kinases (e.g. mTor, ATM) have been found to carry somatic mutations in tumours [30••, 34]. However, it should be appreciated that work to date has focused on their catalytic exons and, although some mutations were found in α, it is now clear that mutations are more common in other none-catalytic exons. Hence it remains possible that potentially significant mutations may occur in other PI3Ks. In keeping with this
Conclusions
Key practical issues for the future remain:
- 1.
What level of PI3K selectivity, if any, will be most effective?
- 2.
Do PTEN wild-type and null cells have similar dependencies on PI3K (α) activity?
- 3.
Precisely what is the frequency with which cancers acquire other activating mutations, which might confer resistance to PI3K inhibitors, in the PI3K pathway?
- 4.
Do cancers tend to acquire PI3K mutations in specific windows in their progression?
However, selective small-molecule inhibitors of PI3Kα have tremendous
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Thanks to Dr Sabina Cosulich for helpful comments.
Glossary
- AMP-PK
- AMP-activated protein kinase
- ATM
- Ataxia telangiectasia mutated complex
- BAD
- Bcl-1-associated death promoter
- DNA-PK
- DNA-dependent protein kinase
- FOXO
- Forkhead box class O transcription factor
- HIF
- Hypoxia-inducible factor
- PDK-1
- Phosphoinositide-dependent kinase 1
- PHLPP
- PH domain leucine-rich repeat protein phosphatase
- PI3K
- Phosphoinositide 3-kinase
- PKB
- Protein kinase B
- PtdIns(3,4,5)P3
- Phosphatidylinositol 3,4,5 trisphosphate
- PTEN
- Phosphatase and tensin homolog deleted on chromosome 10
- SHIP
- SH2 domain-containing
References (51)
- et al.
Targeting the PI3K-Akt pathway in human cancer: rationale and promise
Cancer Cell
(2003) - et al.
Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase
J Biol Chem
(2004) - et al.
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Science
(2005) - et al.
Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate
Mol Cell Biol
(2004) - et al.
Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
Genes Dev
(2004) - et al.
TSC2 mediates cellular energy response to control cell growth and survival
Cell
(2003) - et al.
Rheb fills a GAP between TSC and TOR
Trends Biochem Sci
(2003) - et al.
The LKB1 tumor suppressor negatively regulates mTOR signaling
Cancer Cell
(2004) - et al.
VEGF production by primary human renal proximal tubular cells: requirement of HIF-1, PI3-kinase and MAPKK-1 signaling
Cell Physiol Biochem
(2005) - et al.
Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling
J Invest Dermatol
(2004)
Phosphatidylinositol 3′-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells
Cancer Res
Mutation of the PIK3CA gene in ovarian and breast cancer
Cancer Res
The PIK3CA gene is mutated with high frequency in human breast cancers
Cancer Biol Ther
Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment
Biochem Soc Trans
Phosphoinositide 3-kinases as targets for therapeutic intervention
Curr Pharm Des
Cancer genes and the pathways they control
Nat Med
Mutation analysis of SHIP gene in acute leukemia
Zhongguo Shi Yan Xue Ye Xue Za Zhi
PI 3-kinase, Akt and cell survival
Semin Cell Dev Biol
PHLPP: A novel phosphatase that directly dephosphorylates Akt, promotes apoptosis, and supresses tumour Ggrowth
Mol Cell
Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression
Am J Respir Crit Care Med
The phosphatidylinositol 3-Kinase AKT pathway in human cancer
Nat Rev Cancer
Transformation potential of Ras isoforms correlates with activation of phosphatidylinositol 3-kinase but not ERK
J Biol Chem
Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression
Oncogene
mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery
Cell
Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control
Mol Cell
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