Phosphoinositide 3-kinases as drug targets in cancer

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The past two years have seen phosphoinositide 3-kinases (PI3Ks) move from being seen as potential targets for chemotherapeutics, to one of them — PI3Kα — being generally accepted as validated. A huge amount of work indicated that there was an important role for PI3Ks in tumour progression and, particularly, in the control of proliferation, survival and regulation of the potential oncogene PKB. These links were further strengthened by studies showing that the tumour suppressor, PTEN, is an antagonist of PI3K signalling and that somatic mutations of p110α (PIK3CA) are present in a variety of cancers. We now know that three of the most frequent mutations in cancer constitutively activate PI3Kα and, when expressed in cells, they drive the oncogenic transformation and chronic activation of downstream signalling by molecules such as PKB, S6K and 4E bp1 that is commonly seen in cancer cells. A large body of research into the cellular roles of PI3Ks has also further validated them as potential foci for cancer chemotherapy, with several additional PI3K effectors controlling cell proliferation and apoptosis having been described. Furthermore, molecules important to the processes of metastasis, development of multi-drug resistance, the ‘Warburg effect’, angiogenesis and cell growth (i.e. distinct to proliferation) have been found to depend upon, or to be driven by, PI3K activity.

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

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