PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting

Journal name:
Nature Reviews Cancer
Volume:
15,
Pages:
7–24
Year published:
DOI:
doi:10.1038/nrc3860
Published online

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most common events in human cancers. In this Review, we discuss recent advances in our knowledge of the roles of specific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can be upregulated, and the current state and future potential of targeting this pathway in the clinic.

At a glance

Figures

  1. The PI3K family comprises several classes and isoforms.
    Figure 1: The PI3K family comprises several classes and isoforms.

    Phosphatidylinositol 3-kinases (PI3Ks) are classified on the basis of their substrate specificities and structures. In vivo, class IA and IB PI3Ks phosphorylate phosphatidylinositide 4,5-bisphosphate (PtdIns(4,5)P2), and class III PI3Ks phosphorylate PtdIns. Some evidence suggests that class II PI3Ks may also preferentially phosphorylate PtdIns in vivo8, 9, 10. Class IA PI3Ks are heterodimers of a p110 catalytic subunit and a p85-type regulatory subunit. Class IA catalytic isoforms (p110α, p110β and p110δ) have a p85-binding domain (p85-BD), a RAS-binding domain (RBD), a helical domain and a catalytic domain. Class IA p85 regulatory isoforms (p85α, p85β, p55α, p55γ and p50α) have an inter-SH2 (iSH2) domain that binds to class IA catalytic subunits, flanked by SH2 domains that bind to phosphorylated YXXM motifs. The longer isoforms, p85α and p85β, additionally have amino-terminal SH3 and breakpoint cluster homology (BH) domains. Class IB PI3Ks are heterodimers of a p110γ catalytic subunit and a p101 or p87 regulatory subunit. The p110γ subunit has an RBD, a helical domain and a catalytic domain. The domain structures of p101 and p87 are not fully known, but a carboxy-terminal region of p101 has been shown to bind to Gβγ subunits120. The monomeric class II isoforms (PI3K-C2α, PI3K-C2β and PI3K-C2γ) have an RBD, a helical domain and a catalytic domain. VPS34 (the only class III PI3K) has helical and catalytic domains. VPS34 forms a constitutive heterodimer with the myristoylated, membrane- associated VPS15 protein. Other indicated domains include proline-rich (P) domains, membrane-interacting (C2) domains and Phox homology (PX) domains. Figure adapted from Ref. 2, Nature Publishing Group.

  2. Signalling by class I, II and III PI3K isoforms.
    Figure 2: Signalling by class I, II and III PI3K isoforms.

    a | Upon receptor tyrosine kinase (RTK) or G-protein coupled receptor (GPCR) activation, class I phosphatidylinositol 3-kinases (PI3Ks) are recruited to the plasma membrane by interaction with phosphorylated YXXM motifs on RTKs or their adaptors, or with GPCR-associated Gβγ subunits. There, they phosphorylate phosphatidylinositide (PtdIns) 4,5-bisphosphate (shown as PIP2) to generate PtdIns(3,4,5)P3 (shown as PIP3), a second messenger that activates a number of AKT-dependent and AKT-independent downstream signalling pathways; these regulate diverse cellular functions, including growth, metabolism, motility, survival and transformation. The PTEN lipid phosphatase removes the 3′ phosphate from PtdIns(3,4,5)P3 to inactivate class I PI3K signalling. b |Class II PI3Ks are not well understood but may be activated by a number of different stimuli, including hormones, growth factors, chemokines, cytokines, phospholipids and calcium (Ca2+). Although class II PI3Ks can phosphorylate both PtdIns and PtdIns(4)P in vitro, this class may preferentially phosphorylate PtdIns (shown as PI) to generate PtdIns(3)P (shown as PIP) in vivo8, 9, 10. Class II PI3Ks regulate cellular functions including glucose transport, endocytosis, cell migration and survival. Myotubularin (MTM) family phosphatases remove the 3′ phosphate from PtdIns(3)P to inactivate class II PI3K signalling. c | The class III VPS34–VPS15 heterodimer is found in distinct multiprotein complexes, which have specific cellular functions. VPS34 may be activated by stimuli including amino acids, glucose and other nutrients, and it phosphorylates PtdIns (shown as PI) to generate PtdIns(3)P. It has crucial roles in autophagy, endosomal trafficking and phagocytosis. MTM family phosphatases remove the 3′ phosphate from PtdIns(3)P to inactivate class III PI3K signalling. Part a adapted from Ref. 2, Nature Publishing Group.

  3. Divergent roles of class I PI3K catalytic isoforms in different signalling contexts.
    Figure 3: Divergent roles of class I PI3K catalytic isoforms in different signalling contexts.

    a | Class I phosphatidylinositol 3-kinases (PI3Ks) mediate signalling downstream of receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) and small GTPases. Left: p85 regulatory subunits bind to phosphorylated YXXM motifs on activated RTKs. As p110α, p110β and p110δ bind to p85, these isoforms mediate signalling downstream of RTKs. Recent evidence also suggests that p87–p110γ may be activated by certain RTKs110. Middle: small GTPases synergize with RTK and GPCR signals to directly activate PI3Ks by interacting with their RAS-binding domains (RBDs). Isoforms p110α, p110δ and p110γ bind to RAS family GTPases, while p110β binds to the RHO family GTPases RAC1 and CDC42 (Ref. 143). Right:Gα and Gβγ proteins dissociate from activated GPCRs. Catalytic isoforms p110β and p110γ, and regulatory isoform p101, directly bind to and are activated by Gβγ. The p110δ isoform may be activated downstream of GPCRs, but the mechanism is unknown126, 127, 128. Gα proteins have been reported to directly bind to and inhibit p110α129, 130, 131. b | Competition model for p110α and p110β regulation of RTK signalling96 is shown. Both p85–p110α and p85–p110β compete for phosphorylated YXXM sites on activated RTKs. However, the maximal specific activity and enzymatic rate of p110α are higher than those of p110β108,109, and RTK-associated p110α may have higher lipid kinase activity than p110β96. In this model, loss or inactivation of p110α or p110β differentially modulates RTK signalling. Knockout (KO) of p110α allows all sites to be occupied by the less active p110β subunit, decreasing RTK output. Conversely, KO of p110β allows all sites to be bound by the more active p110α subunit, increasing RTK output. Genetically or pharmacologically inactivated p110α or p110β can still bind to RTKs but cannot signal, reducing RTK output. Part a adapted from Ref. 3, Nature Publishing Group.

  4. An overview of PI3K inhibitors and their combination with other therapeutics.
    Figure 4: An overview of PI3K inhibitors and their combination with other therapeutics.

    a | Molecular contexts dictate applications for isoform-selective phosphatidylinositol 3-kinase (PI3K) inhibitors. Light orange boxes: upregulation or mutation of receptor tyrosine kinases (RTKs), oncogenic RAS mutations or activating p110α mutations all increase phosphatidylinositide (3,4,5) triphosphate (PtdIns(3,4,5)P3) production through p110α, which can be amplified by mutation or loss of PTEN. In these contexts, use of p110α-selective inhibitors is effective. Dark blue boxes: in the absence of other oncogenic alterations, loss or mutation of PTEN increases PtdIns(3,4,5)P3 production through p110β, perhaps because of RAC1- or CDC42-mediated p110β activation, or the basal activity of p110β. In this context, use of p110β-selective inhibitors is effective. Dark orange boxes: upregulation or mutation of B cell receptors (BCRs), cytokine receptors or other immune cell surface markers increases PtdIns(3,4,5)P3 production through p110δ. In this context, use of p110δ-selective inhibitors is effective. b | Rational combination of PI3K inhibitors and other targeted therapeutics is shown. Pan-PI3K and dual pan-PI3K and mTOR inhibitors are currently being tested in clinical trials (white box). These agents are being combined with RTK inhibitors (light turquoise boxes), inhibitors of other membrane- associated proteins (dark turquoise boxes), mTOR-selective inhibitors (dark orange box), RAS–RAF–MEK–ERK-pathway inhibitors (light orange boxes), hormone signalling inhibitors (dark blue boxes) and other agents inhibiting the cell cycle, apoptosis machinery or other signalling pathways (purple boxes). Coloured symbols indicate targeted therapeutics currently in clinical trials for combination with the designated PI3K inhibitor (for further details, see Supplementary information S3 (table)). CDK4, cyclin-dependent kinase 4; EGFR, epithelial growth factor receptor; ER, oestrogen receptor; FGFR, fibroblast growth factor receptor; HSP90, heat shock protein 90; IGF1R, insulin-like growth factor 1 receptor; NF-κB, nuclear factor κB; PARP, poly-(ADP-ribose) polymerase; SYK, spleen tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.

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Affiliations

  1. Department of Cancer Biology, Dana–Farber Cancer Institute, Boston, Massachusetts 02215, USA.

    • Lauren M. Thorpe,
    • Haluk Yuzugullu &
    • Jean J. Zhao
  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Lauren M. Thorpe,
    • Haluk Yuzugullu &
    • Jean J. Zhao
  3. Program in Virology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Lauren M. Thorpe

Competing interests statement

The authors declare no competing interests.

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Author details

  • Lauren M. Thorpe

    Lauren M. Thorpe received her B.S. in Biological Sciences in 2008 from Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. She is now completing her Ph.D. in the laboratory of J. J. Zhao at Harvard Medical School, Boston, Massachusetts, USA. Her work has focused on understanding the role of p85 regulatory isoforms in modulating physiological and pathophysiological PI3K signals.

  • Haluk Yuzugullu

    Haluk Yuzugullu is a postdoctoral fellow in the laboratory of J. J. Zhao at the Dana–Farber Cancer Institute and Harvard Medical School Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts, USA. His research focuses on cancer cell signalling and discovery of potential drug targets using mouse models of cancer.

  • Jean J. Zhao

    Jean J. Zhao is an associate professor in the Department of Cancer Biology at the Dana–Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, Boston, Massachusetts, USA. She received her Ph.D. from Tufts Medical School, Boston, Massachusetts, USA, and did postdoctoral research with Thomas Roberts at the Dana–Farber Cancer Institute. Her research focuses on understanding the roles of key kinases, particularly phosphatidylinositol 3-kinase (PI3K), in normal tissue physiology and cancer pathogenesis. Jean J. Zhao's homepage.

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  1. Supplementary information S1 (357 KB)

    Class I PI3K isoform alterations in cancer

  2. Supplementary information S2 (286 KB)

    Genetically engineered mouse models of PI3K isoforms in cancer

  3. Supplementary information S3 (399 KB)

    Combination of PI3K inhibitors with other targeted therapies in the clinic

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