Review
Cancer-specific mutations in phosphatidylinositol 3-kinase

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Cancer-specific mutations in the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) p110α occur in diverse tumors in frequencies that can exceed 30%. The majority of these mutations map to one of three hot spots in the gene, and the rest are distributed over much of the PI3K coding sequence. Most of the cancer-specific mutations induce a gain of function that results in oncogenicity, elevated lipid kinase activity and constitutive signaling through the kinases Akt and TOR. The location of the mutations on a model structure of p110α indicates several distinct mechanisms for the gain of function. The mutated p110α proteins are promising cancer targets. Although identification of mutant-specific small-molecule inhibitors seems technically challenging, the therapeutic benefits from such inhibitors could be extremely important.

Section snippets

Class I PI3Ks – a potential target for new cancer therapies?

Class I phosphatidylinositol 3-kinases (PI3Ks) form a family of dimeric cellular signaling components that consist of a regulatory and a catalytic subunit. They possess both lipid and protein kinase activity. PI3Ks regulate diverse cellular functions including proliferation, survival, metabolism and motility 1, 2, 3, 4. (For an overview of the canonical PI3K signaling pathways, see Figure 1.) The catalytic subunit p110α of class I PI3K stands out because of its role in transmitting cellular

PI3K and cancer: an established link

PI3K has long been associated with cancer. Early evidence for such a connection was the association of phosphatidylinositol kinase activity with two viral oncoproteins, the Src protein of Rous sarcoma virus and the middle T protein of polyoma virus 9, 10, 11, 12. This interaction is mediated by the regulatory subunit p85 of PI3K, which contains Src homology 2 (SH2) domains that bind to phosphotyrosines on the viral oncoproteins and bring the catalytic subunit p110α of PI3K into these molecular

Mutations in p110α: occurrence in different cancers and mapping on PIK3CA

The identification of cancer-specific mutations in p110α was a seminal discovery [8]. The mutations were found in a fraction of commonly occurring human tumors. A particularly interesting aspect of these p110α mutations is their preferred location in three mutational hot spots within the coding region of PIK3CA. This distribution indicates that certain mutations confer a selective advantage on the cell and would therefore be encountered more frequently. These discoveries provided strong support

Biological and biochemical activities of the p110α hot-spot mutants

The p110α hot-spot mutants E542K, E545K and H1047R have been extensively studied in cells, animals and in vitro. They induce oncogenic transformation of human mammary epithelial cells, primary chicken embryo fibroblasts and NIH3T3 cells 44, 45, 46, 47. The mutant-transformed cells are capable of anchorage-independent growth, show reduced dependence on growth factors and enhanced resistance to apoptosis. They are tumorigenic in mice and in chickens 45, 48. Mutant p110α also functions to promote

Rare mutations in PIK3CA also show gain of function

Several rare mutations in the gene encoding p110α have now been studied, and all except one (H701P) show some gain of function. They can transform NIH3T3 cells or primary chicken embryo fibroblasts 47, 51. Most of them induce growth factor-independent phosphorylation of Akt and p70S6K. They also show increased levels of lipid kinase activity. Both oncogenic transformation and Akt signaling mediated by rare mutants of p110α are rapamycin-sensitive. However, in rare mutants the increases in

Modeling mutant locations and the molecular mechanisms of the gain of function in p110α

More than 80 cancer-specific missense mutations have been identified in PIK3CA (http://www.sanger.ac.uk/genetics/CGP/cosmic/). Their locations are spread over the entire coding sequence of the gene, with the notable exception of the Ras-binding domain. If the mutations studied to date are a representative example of all PIK3CA mutations, then many of the other mutations distributed over the PIK3CA coding sequence must also cause a gain of function. The multiplicity of these mutations makes the

Mutants in p110α as cancer targets

PI3K is widely recognized as an attractive drug target 9, 28, 29, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63. Because the four isoforms of class I p110 – α, β, γ and δ – have non-redundant functions, isoform-specificity is an important prerequisite for any drug candidate 5, 31, 32, 64, 65. A comparative study of the p110 isoforms with diverse chemotypes has defined elements of selective inhibition and singled out the α isoform as the dominant regulator of cell growth [58]. Isoform-specific

Concluding remarks

Mutant PI3K as a cancer target defines an important and urgent goal for biologists and chemists. This task is scientifically and technically daunting, but should prove to be clinically rewarding. Inhibition of gain-of-function mutants of this kinase could provide treatments for a diverse range of cancers, and thus improve current therapeutic options. A serious obstacle to the identification of mutant-specific small-molecule inhibitors and to the understanding of mutant-mediated gain of function

Acknowledgements

This work is supported by grants from the National Cancer Institute and the Stein Fund. Work of M-A.E. is supported by the National Institutes of Health, Protein Structure Initiative (Grant number U54 GM074898). This is manuscript number 18717 of The Scripps Research Institute.

References (84)

  • Y. Samuels

    Mutant PIK3CA promotes cell growth and invasion of human cancer cells

    Cancer Cell

    (2005)
  • C.J. Morrow

    Comparison of phosphatidylinositol-3-kinase signalling within a panel of human colorectal cancer cell lines with mutant or wild-type PIK3CA

    FEBS Lett.

    (2005)
  • L. Stephens

    Phosphoinositide 3-kinases as drug targets in cancer

    Curr. Opin. Pharmacol.

    (2005)
  • P.K. Vogt

    Phosphoinositide 3-kinase: from viral oncoprotein to drug target

    Virology

    (2006)
  • J. Luo

    Targeting the PI3K-Akt pathway in human cancer: rationale and promise

    Cancer Cell

    (2003)
  • Z.A. Knight

    A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling

    Cell

    (2006)
  • M.P. Wymann

    Phosphoinositide 3-kinase signaling – which way to target?

    Trends Pharmacol. Sci.

    (2003)
  • G.D. Prestwich

    Phosphoinositide signaling; from affinity probes to pharmaceutical targets

    Chem. Biol.

    (2004)
  • L. Bi

    Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase

    J. Biol. Chem.

    (1999)
  • M. Hayakawa

    Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110α inhibitors

    Bioorg. Med. Chem.

    (2007)
  • M. Hayakawa

    Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors

    Bioorg. Med. Chem.

    (2006)
  • Q.W. Fan

    A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma

    Cancer Cell

    (2006)
  • H.C. Kolb et al.

    The growing impact of click chemistry on drug discovery

    Drug Discov. Today

    (2003)
  • F.B. Hickey et al.

    BCR–ABL regulates phosphatidylinositol 3-kinase–p110γ transcription and activation and is required for proliferation and drug resistance

    J. Biol. Chem.

    (2006)
  • P. Sujobert

    Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia

    Blood.

    (2005)
  • L.C. Cantley

    The phosphoinositide 3-kinase pathway

    Science

    (2002)
  • J.A. Engelman

    The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

    Nat. Rev. Genet.

    (2006)
  • B. Vanhaesebroeck

    Synthesis and function of 3-phosphorylated inositol lipids

    Annu. Rev. Biochem.

    (2001)
  • L.C. Foukas

    Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation

    Nature

    (2006)
  • J.J. Zhao

    The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • Y. Samuels et al.

    Oncogenic mutations of PIK3CA in human cancers

    Cell Cycle

    (2004)
  • Y. Samuels

    High frequency of mutations of the PIK3CA gene in human cancers

    Science

    (2004)
  • J.J. Zhao et al.

    PI3 kinases in cancer: from oncogene artifact to leading cancer target

    Sci. STKE

    (2006)
  • D.R. Kaplan

    Phosphatidylinositol metabolism and polyoma-mediated transformation

    Proc. Natl. Acad. Sci. U. S. A.

    (1986)
  • Y. Sugimoto

    Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol

    Proc. Natl. Acad. Sci. U. S. A.

    (1984)
  • M. Whitman

    Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation

    Nature

    (1985)
  • A. Klippel

    The C-terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor β receptor

    Mol. Cell. Biol.

    (1992)
  • P. Hu

    Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors

    Mol. Cell. Biol.

    (1992)
  • C. Jimenez

    Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase

    EMBO J.

    (1998)
  • H.W. Chang

    Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase

    Science

    (1997)
  • M. Aoki

    A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • M. Aoki

    The akt kinase: molecular determinants of oncogenicity

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)

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