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

Journal name:
Nature Reviews Cancer
Year published:
Published online


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


  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.


  1. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genet. 7, 606619 (2006).
  2. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Rev. Drug Discov. 8, 627644 (2009).
  3. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. & Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nature Rev. Mol. Cell Biol. 11, 329341 (2010).
  4. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550562 (2009).
  5. Mellor, P., Furber, L. A., Nyarko, J. N. & Anderson, D. H. Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking. Biochem. J. 441, 2337 (2012).
  6. Okkenhaug, K. & Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nature Rev. Immunol. 3, 317330 (2003).
  7. Falasca, M. & Maffucci, T. Regulation and cellular functions of class II phosphoinositide 3-kinases. Biochem. J. 443, 587601 (2012).
  8. Falasca, M. et al. The role of phosphoinositide 3-kinase C2 α in insulin signaling. J. Biol. Chem. 282, 2822628236 (2007).
  9. Maffucci, T. et al. Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J. Cell Biol. 169, 789799 (2005).
  10. Yoshioka, K. et al. Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nature Med. 18, 15601569 (2012).
  11. Franco, I. et al. PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Dev. Cell 28, 647658 (2014).
  12. Schu, P. V. et al. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260, 8891 (1993).
  13. Volinia, S. et al. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 14, 33393348 (1995).
  14. Backer, J. M. The regulation & function of class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 117 (2008).
  15. Blondeau, F. et al. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum. Mol. Genet. 9, 22232229 (2000).
  16. Lu, N. et al. Two PI 3-kinases and one PI 3-phosphatase together establish the cyclic waves of phagosomal PtdIns3P critical for the degradation of apoptotic cells. PLoS Biol. 10, e1001245 (2012).
  17. Velichkova, M. et al. Drosophila Mtm and class II PI3K coregulate a PI3P pool with cortical and endolysosomal functions. J. Cell Biol. 190, 407425 (2010).
  18. Cao, C., Backer, J. M., Laporte, J., Bedrick, E. J. & Wandinger-Ness, A. Sequential actions of myotubularin lipid phosphatases regulate endosomal PI3P and growth factor receptor trafficking. Mol. Biol. Cell 19, 33343346 (2008).
  19. Parsons, R. Human cancer, PTEN and the PI-3 kinase pathway. Semin. Cell Dev. Biol. 15, 171176 (2004).
  20. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol. 13, 283296 (2012).
  21. Chang, H. W. et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI3-kinase. Science 276, 18481850 (1997).
  22. Klippel, A. et al. Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways. Mol. Cell. Biol. 16, 41174127 (1996).
  23. Zhao, J. J. et al. The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl Acad. Sci. USA 102, 1844318448 (2005).
  24. Zhao, J. J. et al. Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell 3, 483495 (2003).
  25. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
  26. Isakoff, S. J. et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 65, 1099211000 (2005).
  27. Kang, S., Bader, A. G. & Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl Acad. Sci. USA 102, 802807 (2005).
  28. Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med. 14, 13511356 (2008).
  29. Liu, P. et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nature Med. 17, 11161120 (2011).
    This study used an inducible GEMM of PIK3CAH1047R-driven mammary tumours to identify potential mechanisms of resistance to PI3K-targeted therapy.
  30. Yuan, W. et al. Conditional activation of Pik3caH1047R in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogene 32, 318326 (2013).
  31. Kinross, K. M. et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Invest. 122, 553557 (2012).
  32. Wu, R. et al. Type I to type II ovarian carcinoma progression: mutant Trp53 or Pik3ca confers a more aggressive tumor phenotype in a mouse model of ovarian cancer. Am. J. Pathol. 182, 13911399 (2013).
  33. Huang, C. H. et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 17441748 (2007).
  34. Zhao, L. & Vogt, P. K. Hot-spot mutations in p110α of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle 9, 596600 (2010).
  35. Miled, N. et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239242 (2007).
  36. Burke, J. E., Perisic, O., Masson, G. R., Vadas, O. & Williams, R. L. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110a (PIK3CA). Proc. Natl Acad. Sci. USA 109, 1525915264 (2012).
  37. Hao, Y. et al. Gain of interaction with IRS1 by p110a-helical domain mutants is crucial for their oncogenic functions. Cancer Cell 23, 583593 (2013).
  38. Mandelker, D. et al. A frequent kinase domain mutation that changes the interaction between PI3Ka and the membrane. Proc. Natl Acad. Sci. USA 106, 1699617001 (2009).
  39. Orloff, M. S. et al. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 92, 7680 (2013).
  40. Kurek, K. C. et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90, 11081115 (2012).
  41. Riviere, J. B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genet. 44, 934940 (2012).
  42. Rios, J. J. et al. Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. Hum. Mol. Genet. 22, 444451 (2013).
  43. Angulo, I. et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342, 866871 (2013).
  44. Lucas, C. L. et al. Dominant-activating germline mutations in the gene encoding the PI3K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nature Immunol. 15, 8897 (2014).
  45. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869873 (2010).
  46. Dbouk, H. A. et al. Characterization of a tumor-associated activating mutation of the p110β PI3-kinase. PLoS ONE 8, e63833 (2013).
  47. Dbouk, H. A., Pang, H., Fiser, A. & Backer, J. M. A biochemical mechanism for the oncogenic potential of the p110β catalytic subunit of phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 107, 1989719902 (2010).
  48. Zhang, X. et al. Structure of lipid kinase p110β–p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567578 (2011).
    In references 47 and 48, biochemical and structural studies were used to show that p85 inhibition of p110β is different from its inhibition of p110α.
  49. Vogt, P. K. PI3K p110β: more tightly controlled or constitutively active? Mol. Cell 41, 499501 (2011).
    This paper provides a commentary on how the studies in references 47 and 48 together may indicate that p110β is a more basally active isoform than p110α.
  50. Sawyer, C. et al. Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110δ. Cancer Res. 63, 16671675 (2003).
  51. Kang, S., Denley, A., Vanhaesebroeck, B. & Vogt, P. K. Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 103, 12891294 (2006).
  52. Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 74267429 (2001).
  53. Cheung, L. W. et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 1, 170185 (2011).
  54. Urick, M. E. et al. PIK3R1 (p85α) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 71, 40614067 (2011).
  55. Jaiswal, B. S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463474 (2009).
  56. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 10611068 (2008).
  57. Cizkova, M. et al. PIK3R1 underexpression is an independent prognostic marker in breast cancer. BMC Cancer 13, 545 (2013).
  58. Wu, H. et al. Regulation of Class IA PI3-kinases: C2 domain-iSH2 domain contacts inhibit p85–p110α and are disrupted in oncogenic p85 mutants. Proc. Natl Acad. Sci. USA 106, 2025820263 (2009).
    References 53, 55 and 58 show the transforming potential of cancer-associated iSH2 domain p85α mutants.
  59. Sun, M., Hillmann, P., Hofmann, B. T., Hart, J. R. & Vogt, P. K. Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α. Proc. Natl Acad. Sci. USA 107, 1554715552 (2010).
  60. Taniguchi, C. M. et al. The phosphoinositide 3-kinase regulatory subunit p85α can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res. 70, 53055315 (2010).
  61. Luo, J. et al. Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/− mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 102, 1023810243 (2005).
  62. Luo, J. & Cantley, L. C. The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer. Cell Cycle 4, 13091312 (2005).
  63. Cortes, I. et al. p85β phosphoinositide 3-kinase subunit regulates tumor progression. Proc. Natl Acad. Sci. USA 109, 1131811323 (2012).
  64. Biswas, K. et al. Essential role of class II phosphatidylinositol-3-kinase-C2α in sphingosine 1-phosphate receptor-1-mediated signaling and migration in endothelial cells. J. Biol. Chem. 288, 23252339 (2013).
  65. Katso, R. M. et al. Phosphoinositide 3-Kinase C2β regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms. Mol. Biol. Cell 17, 37293744 (2006).
  66. Elis, W. et al. Down-regulation of class II phosphoinositide 3-kinase α expression below a critical threshold induces apoptotic cell death. Mol. Cancer Res. 6, 614623 (2008).
  67. Diouf, B. et al. Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nature Med. 17, 12981303 (2011).
  68. Knobbe, C. B. & Reifenberger, G. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol. 13, 507518 (2003).
  69. Rao, S. K., Edwards, J., Joshi, A. D., Siu, I. M. & Riggins, G. J. A survey of glioblastoma genomic amplifications and deletions. J. Neurooncol. 96, 169179 (2010).
  70. Nobusawa, S. et al. Intratumoral patterns of genomic imbalance in glioblastomas. Brain Pathol. 20, 936944 (2010).
  71. Liu, P. et al. Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing. Carcinogenesis 33, 12701276 (2012).
  72. Harada, K., Truong, A. B., Cai, T. & Khavari, P. A. The class II phosphoinositide 3-kinase C2β is not essential for epidermal differentiation. Mol. Cell. Biol. 25, 1112211130 (2005).
  73. Harris, D. P. et al. Requirement for class II phosphoinositide 3-kinase C2α in maintenance of glomerular structure and function. Mol. Cell. Biol. 31, 6380 (2011).
  74. Norris, F. A., Atkins, R. C. & Majerus, P. W. The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family. J. Biol. Chem. 272, 2385923864 (1997).
  75. Gewinner, C. et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16, 115125 (2009).
  76. Fedele, C. G. et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc. Natl Acad. Sci. USA 107, 2223122236 (2010).
  77. Stjernstrom, A. et al. Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung. Cancer Med. 3, 337348 (2014).
  78. Hodgson, M. C. et al. Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer Res. 71, 572582 (2011).
  79. Hirsch, D. S., Shen, Y., Dokmanovic, M. & Wu, W. J. pp60c-Src phosphorylates and activates vacuolar protein sorting 34 to mediate cellular transformation. Cancer Res. 70, 59745983 (2010).
  80. Denley, A., Gymnopoulos, M., Kang, S., Mitchell, C. & Vogt, P. K. Requirement of phosphatidylinositol(3,4,5)trisphosphate in phosphatidylinositol 3-kinase-induced oncogenic transformation. Mol. Cancer Res. 7, 11321138 (2009).
  81. Wei, Y. et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 12691284 (2013).
  82. Bi, L., Okabe, I., Bernard, D. J. & Nussbaum, R. L. Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI3-kinase. Mamm. Genome 13, 169172 (2002).
  83. Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A. & Nussbaum, R. L. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase. J. Biol. Chem. 274, 1096310968 (1999).
  84. Ciraolo, E. et al. Phosphoinositide 3-kinase p110β activity: key role in metabolism and mammary gland cancer but not development. Sci. Signal. 1, ra3 (2008).
  85. Ciraolo, E. et al. Essential role of the p110β subunit of phosphoinositide 3-OH kinase in male fertility. Mol. Biol. Cell 21, 704711 (2010).
  86. Clayton, E. et al. A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation. J. Exp. Med. 196, 753763 (2002).
  87. Ali, K. et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 431, 10071011 (2004).
  88. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 10311034 (2002).
  89. Jou, S. T. et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22, 85808591 (2002).
  90. Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 10401046 (2000).
  91. Yum, H. K. et al. Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury. J. Immunol. 167, 66016608 (2001).
  92. Martin, A. L., Schwartz, M. D., Jameson, S. C. & Shimizu, Y. Selective regulation of CD8 effector T cell migration by the p110γ isoform of phosphatidylinositol 3-kinase. J. Immunol. 180, 20812088 (2008).
  93. Rameh, L. E., Chen, C. S. & Cantley, L. C. Phosphatidylinositol (3,4,5)P3 interacts with SH2 domains and modulates PI3-kinase association with tyrosine-phosphorylated proteins. Cell 83, 821830 (1995).
  94. Yu, J., Wjasow, C. & Backer, J. M. Regulation of the p85/p110α phosphatidylinositol 3′-kinase. Distinct roles for the n-terminal and c-terminal SH2 domains. J. Biol. Chem. 273, 3019930203 (1998).
  95. Yu, J. et al. Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit. Mol. Cell. Biol. 18, 13791387 (1998).
  96. Utermark, T. et al. The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev. 26, 15731586 (2012).
    In this study, GEMMs of oncogenic RTK-driven mammary tumors were used to identify a new mechanism in which p110β competes with p110α for RTK binding to modulate lipid kinase activity in response to RTK activation.
  97. Zhao, J. J. et al. The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc. Natl Acad. Sci. USA 103, 1629616300 (2006).
  98. Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733747 (2006).
  99. Foukas, L. C. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366370 (2006).
  100. Sopasakis, V. R. et al. Specific roles of the p110α isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell. Metab. 11, 220230 (2010).
  101. Graupera, M. et al. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453, 662666 (2008).
  102. Jia, S. et al. Essential roles of PI3K–p110β in cell growth, metabolism and tumorigenesis. Nature 454, 776779 (2008).
  103. Guillermet-Guibert, J. et al. The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ. Proc. Natl Acad. Sci. USA 105, 82928297 (2008).
  104. Chaussade, C. et al. Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem. J. 404, 449458 (2007).
  105. Papakonstanti, E. A. et al. Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages. J. Cell Sci. 121, 41244133 (2008).
  106. Vanhaesebroeck, B. et al. Distinct PI3Ks mediate mitogenic signalling and cell migration in macrophages. Nature Cell Biol. 1, 6971 (1999).
  107. Geering, B., Cutillas, P. R., Nock, G., Gharbi, S. I. & Vanhaesebroeck, B. Class IA phosphoinositide 3-kinases are obligate p85–p110 heterodimers. Proc. Natl Acad. Sci. USA 104, 78097814 (2007).
  108. Meier, T. I. et al. Cloning, expression, purification, and characterization of the human class Ia phosphoinositide 3-kinase isoforms. Protein Expr. Purif. 35, 218224 (2004).
  109. Beeton, C. A., Chance, E. M., Foukas, L. C. & Shepherd, P. R. Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110α and p110β catalytic subunits of class-Ia phosphoinositide 3-kinases. Biochem. J. 350, 353359 (2000).
  110. Schmid, M. C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715727 (2011).
  111. Bohnacker, T. et al. PI3Kγ adaptor subunits define coupling to degranulation and cell motility by distinct PtdIns(3,4,5)P3 pools in mast cells. Sci. Signal. 2, ra27 (2009).
  112. Voigt, P., Dorner, M. B. & Schaefer, M. Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase γ that is highly expressed in heart and interacts with PDE3B. J. Biol. Chem. 281, 99779986 (2006).
  113. Shymanets, A. et al. p87 and p101 subunits are distinct regulators determining class IB phosphoinositide 3-kinase (PI3K) specificity. J. Biol. Chem. 288, 3105931068 (2013).
  114. Kurig, B. et al. Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110γ. Proc. Natl Acad. Sci. USA 106, 2031220317 (2009).
  115. Brock, C. et al. Roles of Gβγ in membrane recruitment and activation of p110 γ/p101 phosphoinositide 3-kinase g. J. Cell Biol. 160, 8999 (2003).
  116. Stoyanov, B. et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269, 690693 (1995).
  117. Maier, U., Babich, A. & Nurnberg, B. Roles of non-catalytic subunits in Gβγ-induced activation of class I phosphoinositide 3-kinase isoforms β and γ. J. Biol. Chem. 274, 2931129317 (1999).
  118. Suire, S. et al. p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ. Curr. Biol. 15, 566570 (2005).
  119. Stephens, L. R. et al. The Gβγ sensitivity of a PI3K is dependent upon a tightly associated adaptor, 101. Cell 89, 105114 (1997).
  120. Vadas, O. et al. Molecular determinants of PI3Kγ-mediated activation downstream of G-protein-coupled receptors (GPCRs). Proc. Natl Acad. Sci. USA 110, 1886218867 (2013).
  121. Schmid, M. C. et al. PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth. PLoS ONE 8, e60226 (2013).
  122. Kubo, H., Hazeki, K., Takasuga, S. & Hazeki, O. Specific role for p85/p110β in GTP-binding-protein-mediated activation of Akt. Biochem. J. 392, 607614 (2005).
  123. Kurosu, H. et al. Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110b is synergistically activated by the βγ subunits of G proteins and phosphotyrosyl peptide. J. Biol. Chem. 272, 2425224256 (1997).
  124. Murga, C., Fukuhara, S. & Gutkind, J. S. A novel role for phosphatidylinositol 3-kinase β in signaling from G protein-coupled receptors to Akt. J. Biol. Chem. 275, 1206912073 (2000).
  125. Dbouk, H. A. et al. G protein-coupled receptor-mediated activation of p110β by Gβγ is required for cellular transformation and invasiveness. Sci. Signal. 5, ra89 (2012).
    This study uses hydrogen–deuterium exchange mass spectrometry (HDX-MS) to identify the site on p110β responsible for Gβγ binding, which is not conserved among other class IA p110 isoforms.
  126. Saudemont, A. et al. p110γ and p110δ isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc. Natl Acad. Sci. USA 106, 57955800 (2009).
  127. Reif, K. et al. Cutting edge: differential roles for phosphoinositide 3-kinases, 110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173, 22362240 (2004).
  128. Durand, C. A. et al. Phosphoinositide 3-kinase p110 delta regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses. J. Immunol. 183, 56735684 (2009).
  129. Ballou, L. M., Chattopadhyay, M., Li, Y., Scarlata, S. & Lin, R. Z. Gαq binds to p110α/p85α phosphoinositide 3-kinase and displaces Ras. Biochem. J. 394, 557562 (2006).
  130. Ballou, L. M., Lin, H. Y., Fan, G., Jiang, Y. P. & Lin, R. Z. Activated Gaq inhibits p110 a phosphatidylinositol 3-kinase and Akt. J. Biol. Chem. 278, 2347223479 (2003).
  131. Yeung, W. W. & Wong, Y. H. Gα16 interacts with Class IA phosphatidylinositol 3-kinases and inhibits Akt signaling. Cell Signal 22, 13791387 (2010).
  132. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527532 (1994).
  133. Rodriguez-Viciana, P., Warne, P. H., Vanhaesebroeck, B., Waterfield, M. D. & Downward, J. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J. 15, 24422451 (1996).
  134. Rubio, I., Rodriguez-Viciana, P., Downward, J. & Wetzker, R. Interaction of Ras with phosphoinositide 3-kinase γ. Biochem. J. 326, 891895 (1997).
  135. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinaseγ. Cell 103, 931943 (2000).
  136. Suire, S., Hawkins, P. & Stephens, L. Activation of phosphoinositide 3-kinase γ by Ras. Curr. Biol. 12, 10681075 (2002).
  137. Zhao, L. & Vogt, P. K. Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl Acad. Sci. USA 105, 26522657 (2008).
  138. Denley, A., Kang, S., Karst, U. & Vogt, P. K. Oncogenic signaling of class I PI3K isoforms. Oncogene 27, 25612574 (2008).
  139. Gupta, S. et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell 129, 957968 (2007).
  140. Castellano, E. et al. Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance. Cancer Cell 24, 617630 (2013).
  141. Gritsman, K. et al. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α. J. Clin. Invest. 124, 17941809 (2014).
    References 140 and 141 use GEMMs to show the specific importance of p110α in the development and maintenance of RAS-driven cancers.
  142. Suire, S. et al. Gβγs and the Ras binding domain of p110γ are both important regulators of PI3Kγ signalling in neutrophils. Nature Cell Biol. 8, 13031309 (2006).
  143. Fritsch, R. et al. RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 153, 10501063 (2013).
    This extensive biochemical study identifies RHO but not RAS small GTPases as directly binding and activating p110β through its RBD.
  144. Vanhaesebroeck, B. et al. P110δ, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl Acad. Sci. USA 94, 43304335 (1997).
  145. Murphy, G. A. et al. Involvement of phosphatidylinositol 3-kinase, but not RalGDS, in TC21/R-Ras2-mediated transformation. J. Biol. Chem. 277, 99669975 (2002).
  146. Rodriguez-Viciana, P., Sabatier, C. & McCormick, F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol. Cell. Biol. 24, 49434954 (2004).
  147. Delgado, P. et al. Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nature Immunol. 10, 880888 (2009).
  148. Klarlund, J. K. et al. Signaling by phosphoinositide-3,4,5-trisphosphate through proteins containing pleckstrin and Sec7 homology domains. Science 275, 19271930 (1997).
  149. Welch, H. C. et al. P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809821 (2002).
  150. Krugmann, S. et al. Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol. Cell 9, 95108 (2002).
  151. Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16, 6467 (1997).
  152. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression. Nature Genet. 19, 348355 (1998).
  153. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 2939 (1998).
  154. Kwabi-Addo, B. et al. Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc. Natl Acad. Sci. USA 98, 1156311568 (2001).
  155. Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209221 (2003).
  156. Alimonti, A. et al. Subtle variations in Pten dose determine cancer susceptibility. Nature Genet. 42, 454458 (2010).
  157. Ni, J. et al. Functional characterization of an isoform-selective inhibitor of PI3K–p110β as a potential anticancer agent. Cancer Discov. 2, 425433 (2012).
    This study identifies a novel p110β-selective inhibitor and shows its effectiveness against PTEN-deficient tumours in mice.
  158. Torbett, N. E. et al. A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem. J. 415, 97110 (2008).
  159. Wee, S. et al. PTEN-deficient cancers depend on PIK3CB. Proc. Natl Acad. Sci. USA 105, 1305713062 (2008).
  160. Jia, S. et al. Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov. 3, 4451 (2013).
  161. Berenjeno, I. M. et al. Both p110α and p110β isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. Biochem. J. 442, 151159 (2012).
  162. Schmit, F. et al. PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc. Natl Acad. Sci. USA 111, 63956400 (2014).
    This study uses GEMMs to show that concomitant expression of oncogenic RAS can shift the isoform reliance of PTEN-deficient tumours from p110β to p110α.
  163. Wang, Q., Weisberg, E. & Zhao, J. J. The gene dosage of class Ia PI3K dictates the development of PTEN hamartoma tumor syndrome. Cell Cycle 12, 35893593 (2013).
  164. Wang, Q. et al. Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome. Genes Dev. 27, 15681580 (2013).
    This study identifies specific roles for both p110α and p110β in epidermal compartments of a GEMM of PHTS.
  165. Subramaniam, P. S. et al. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell 21, 459472 (2012).
    This study uses GEMMs to show that both p110δ and p110γ contribute to T-ALL that is driven by PTEN loss.
  166. Weigelt, B., Warne, P. H., Lambros, M. B., Reis-Filho, J. S. & Downward, J. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin. Cancer Res. 19, 35333544 (2013).
  167. Rodon, J., Dienstmann, R., Serra, V. & Tabernero, J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nature Rev. Clin. Oncol. 10, 143153 (2013).
  168. Raynaud, F. I. et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther. 8, 17251738 (2009).
  169. Maira, S. M. et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7, 18511863 (2008).
  170. Fruman, D. A. & Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nature Rev. Drug Discov. 13, 140156 (2014).
  171. Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 9971007 (2014).
  172. Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 10081018 (2014).
    References 171 and 172 report dramatic success in the treatment of patients with B cell malignancies with the p110δ-selective inhibitor idelalisib.
  173. Fruman, D. A. & Cantley, L. C. Idelalisib — a PI3Kδ inhibitor for B-cell cancers. N. Engl. J. Med. 370, 10611062 (2014).
  174. Vanhaesebroeck, B. & Khwaja, A. PI3Kδ inhibition hits a sensitive spot in B cell malignancies. Cancer Cell 25, 269271 (2014).
  175. Ali, K. et al. Inactivation of PI3K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature (2014).
    This paper shows that p110δ inactivation inhibits the growth of certain solid tumours by blocking regulatory T cell-mediated immune suppression in mice.
  176. Juric, D. et al. Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer. Cancer Res. 73, D1D3 (2013).
  177. Busaidy, N. L. et al. Management of metabolic effects associated with anticancer agents targeting the PI3K–Akt–mTOR pathway. J. Clin. Oncol. 30, 29192928 (2012).
  178. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596599 (2010).
  179. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 25072516 (2011).
  180. Sampath, D. et al. Abstract P4-15-02: The PI3K inhibitor GDC-0032 enhances the efficacy of standard of care therapeutics in PI3Kα mutant breast cancer models. Cancer Res. 73, 4-15-02 (2013).
  181. O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 15001508 (2006).
  182. Britschgi, A. et al. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 22, 796811 (2012).
  183. Muranen, T. et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21, 227239 (2012).
  184. Elkabets, M. et al. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci. Transl. Med. 5, 196ra99 (2013).
    This paper identifies mTOR pathway activation as a mechanism of resistance to p110α-selective therapy that can be overcome by mTORC1 inhibition.
  185. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 5871 (2011).
    This paper shows that PI3K–AKT-pathway inhibition induces a feedback loop leading to overexpression and activation of multiple RTKs that can be overcome by combined PI3K and RTK inhibition.
  186. Sergina, N. V. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445, 437441 (2007).
  187. Garrett, J. T. et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc. Natl Acad. Sci. USA 108, 50215026 (2011).
  188. Garrett, J. T. et al. Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110α inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers. Cancer Res. 73, 60136023 (2013).
  189. Tao, J. J. et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci. Signal. 7, ra29 (2014).
  190. Serra, V. et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30, 25472557 (2011).
  191. Will, M. et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS–ERK signaling. Cancer Discov. 4, 334347 (2014).
  192. Ilic, N., Utermark, T., Widlund, H. R. & Roberts, T. M. PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc. Natl Acad. Sci. USA 108, E699E708 (2011).
  193. Muellner, M. K. et al. A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nature Chem. Biol. 7, 787793 (2011).
  194. Tenbaum, S. P. et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nature Med. 18, 892901 (2012).
    In this study, WNT–β-catenin pathway hyperactivation is shown to be a potential mechanism contributing to resistance to PI3K pathway inhibition and metastasis in colon cancer.
  195. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904917 (2011).
  196. Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614620 (2009).
  197. Juric, D. et al. Phase I study of BYL719, an α-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC). Cancer Res. 72, P6-10-07 (2012).
  198. Juric, D. et al. Preliminary safety, pharmacokinetics and anti-tumor activity of BYL719, an α-specific PI3K inhibitor in combination with fulvestrant: results from a phase I study. Cancer Res. 73, 2-16-14 (2013).
  199. Gruber Filbin, M. et al. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nature Med. 19, 15181523 (2013).
  200. Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 10481063 (2012).
  201. Ibrahim, Y. H. et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 10361047 (2012).
    References 200 and 201 show that PI3K inhibition leads to the downregulation of BRCA1 and BRCA2 and subsequent sensitization of tumour cells to PARP inhibitors.
  202. Gonzalez-Billalabeitia, E. et al. Vulnerabilities of PTEN-p53-deficient prostate cancers to compound PARP/PI3K inhibition. Cancer Discov. 8, 896904 (2014).
  203. Rahmani, M. et al. Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism. Cancer Res. 73, 13401351 (2013).
  204. Vora, S. R. et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26, 136149 (2014).

Download references

Author information


  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.

Corresponding author

Correspondence to:

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.

Supplementary information

PDF files

  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

Additional data