Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

PI3K and cancer: lessons, challenges and opportunities

Key Points

  • Mutations that activate the phosphoinositide 3-kinase (PI3K) signalling network are nearly ubiquitous in human cancer.

  • PI3K activation has central physiological roles in many normal cells and tissues, including those of the immune system.

  • Small molecules have been generated that selectively inhibit PI3K, AKT or mammalian target of rapamycin (mTOR) with good pharmacological properties.

  • As single agents, most PI3K–AKT–mTOR inhibitors are cytostatic rather than cytotoxic to cancer cells.

  • Early results from clinical trials show limited activity of these agents as monotherapies, but a striking exception is GS-1101, which is a selective inhibitor of p110δ.

  • Now is the time to re-evaluate strategies to develop and apply PI3K pathway inhibitors for treating cancer.

  • This Review proposes four priorities to guide future efforts in translational and clinical research.

  • The first is biomarker identification, which involves using next-generation sequencing to identify genetic correlates for rare responders.

  • The second is haematological malignancies; following on the success of GS-1101, clinical trials of leukaemia and lymphoma provide advantages for pharmacodynamic monitoring and for harnessing the effects of pathway inhibitors on the tumour microenvironment.

  • The third is immune effects, which involves taking advantage of the cell-extrinsic effects of PI3K–mTOR inhibitors that can enhance antitumour immunity under certain conditions.

  • The last is combination trials; it is likely that PI3K pathway inhibitors will be most effective when applied in combination with other targeted inhibitors. Many such combinations are discussed.

Abstract

The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K–AKT–mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targets in the signalling network and their role in tumour biology.
Figure 2: Complexity, crosstalk and feedback in the PI3K–AKT–mTOR signalling network.
Figure 3: Two arguments for combining TKIs with PI3K–AKT–mTOR inhibitors.
Figure 4: Rationale for BCL-2 antagonist combinations.

References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Beagle, B. & Fruman, D. A. A lipid kinase cousin cooperates to promote cancer. Cancer Cell 19, 693–695 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Soler, A. et al. Inhibition of the p110α isoform of PI3-kinase stimulates nonfunctional tumor angiogenesis. J. Exp. Med. 210, 1937–1945 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hirsch, E., Ciraolo, E., Franco, I., Ghigo, A. & Martini, M. PI3K in cancer–stroma interactions: bad in seed and ugly in soil. Oncogene http://dx.doi.org/10.1038/onc.2013.265 (2013).

  5. Vanhaesebroeck, B. et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535–602 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Zhao, J. J. & Roberts, T. M. PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci. STKE 2006, e52 (2006).

    Article  Google Scholar 

  7. Lemmon, M. A. Membrane recognition by phospholipid-binding domains. Nature Rev. Mol. Cell Biol. 9, 99–111 (2008).

    Article  CAS  Google Scholar 

  8. Samuels, Y. & Ericson, K. Oncogenic PI3K and its role in cancer. Curr. Opin. Oncol. 18, 77–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  Google Scholar 

  10. Lui, V. W. et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 3, 761–769 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550–562 (2009).

    Article  CAS  Google Scholar 

  12. Berndt, A. et al. The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nature Chem. Biol. 6, 244 (2010).

    Article  CAS  Google Scholar 

  13. Huang, C. H. et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 1744–1748 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Miled, N. et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239–242 (2007). References 13 and 14 are two hallmark structural studies of p110α.

    Article  CAS  PubMed  Google Scholar 

  15. Vadas, O., Burke, J. E., Zhang, X., Berndt, A. & Williams, R. L. Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci. Signal. 4, re2 (2011).

    Article  PubMed  CAS  Google Scholar 

  16. Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402, 313–320 (1999). This paper reports first X-ray structure of a class I PI3K.

    Article  CAS  PubMed  Google Scholar 

  17. Wu, H. et al. Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. Proc. Natl Acad. Sci. USA 106, 20258–20263 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang, X. et al. Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567–578 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Garcia-Echeverria, C. & Sellers, W. R. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27, 5511–5526 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Wander, S. A., Hennessy, B. T. & Slingerland, J. M. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest. 121, 1231–1241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Workman, P., Clarke, P. A., Raynaud, F. I. & van Montfort, R. L. Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res. 70, 2146–2157 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Agarwal, R., Carey, M., Hennessy, B. & Mills, G. B. PI3K pathway-directed therapeutic strategies in cancer. Curr. Opin. Investigat. Drugs 11, 615–628 (2010).

    CAS  Google Scholar 

  23. Marone, R., Cmiljanovic, V., Giese, B. & Wymann, M. P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta 1784, 159–185 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Yap, T. A. et al. Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 8, 393–412 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Rodon, J., Dienstmann, R., Serra, V. & Tabernero, J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nature Rev. Clin. Oncol. 10, 143–153 (2013).

    Article  CAS  Google Scholar 

  26. Klempner, S. J., Myers, A. P. & Cantley, L. C. What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. Cancer Discov. 3, 1345–1354 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. 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, 1351–1356 (2008). This paper provides the first proof of concept in vivo for co-targeting PI3K and MEK.

    Article  CAS  PubMed  Google Scholar 

  28. 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, E699–E708 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu, P. et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nature Med. 17, 1116–1120 (2011). This reversible PIK3CA model showed mechanisms of relapse.

    Article  CAS  PubMed  Google Scholar 

  30. 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, 553–557 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tikoo, A. et al. Physiological levels of Pik3ca(H1047R) mutation in the mouse mammary gland results in ductal hyperplasia and formation of ERalpha-positive tumors. PLoS ONE 7, e36924 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fruman, D. A. & Rommel, C. PI3Kδ inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov. 1, 562–572 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Macias-Perez, I. M. & Flinn, I. W. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr. Hematol. Malignancy Rep. 8, 22–27 (2013).

    Article  Google Scholar 

  34. Burger, J. A. Targeting the microenvironment in chronic lymphocytic leukemia is changing the therapeutic landscape. Curr. Opin. Oncol. 24, 643–649 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Riley, J. L. Combination checkpoint blockade — taking melanoma immunotherapy to the next level. N. Engl. J. Med. 369, 187–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. & Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nature Rev. Mol. Cell Biol. 11, 329–341 (2010).

    Article  CAS  Google Scholar 

  39. Fritsch, R. et al. RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 153, 1050–1063 (2013). This paper reports the discovery that RAC and CDC42, and not RAS, contribute to the activation of p110β.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fruman, D. A. Towards an understanding of isoform specificity in phosphoinositide 3-kinase signalling in lymphocytes. Biochem. Soc. Trans. 32, 315–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Hawkins, P. T., Stephens, L. R., Suire, S. & Wilson, M. PI3K signaling in neutrophils. Curr. Top. Microbiol. Immunol. 346, 183–202 (2010).

    CAS  PubMed  Google Scholar 

  42. Okkenhaug, K., Ali, K. & Vanhaesebroeck, B. Antigen receptor signalling: a distinctive role for the p110δ isoform of PI3K. Trends Immunol. 28, 80–87 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Okkenhaug, K. & Fruman, D. A. PI3Ks in lymphocyte signaling and development. Curr. Top. Microbiol. Immunol. 346, 57–85 (2011).

    Google Scholar 

  44. Foukas, L. C., Berenjeno, I. M., Gray, A., Khwaja, A. & Vanhaesebroeck, B. Activity of any class IA PI3K isoform can sustain cell proliferation and survival. Proc. Natl Acad. Sci. USA 107, 11381–11386 (2010). This paper provides evidence for the redundant functions of PI3K isoforms in cell proliferation and survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dbouk, H. A. et al. Characterization of a tumor-associated activating mutation of the p110β PI 3-kinase. PLoS ONE 8, e63833 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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, 170–185 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jaiswal, B. S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463–474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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, 15547–15552 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wee, S. et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69, 4286–4293 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Ludovini, V. et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J. Thorac. Oncol. 6, 707–715 (2011).

    Article  PubMed  Google Scholar 

  51. Suda, K., Mizuuchi, H., Maehara, Y. & Mitsudomi, T. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation — diversity, ductility, and destiny. Cancer Metastasis Rev. 31, 807–814 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Cybulski, N. & Hall, M. N. TOR complex 2: a signaling pathway of its own. Trends Biochem. Sci. 34, 620–627 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zinzalla, V., Stracka, D., Oppliger, W. & Hall, M. N. Activation of mTORC2 by association with the ribosome. Cell 144, 757–768 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Huang, J. & Manning, B. D. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412, 179–190 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Dibble, C. C. et al. TBC1D7 is a third subunit of the TSC1–TSC2 complex upstream of mTORC1. Mol. Cell 47, 535–546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Guertin, D. A. et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15, 148–159 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nardella, C. et al. Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci. Signal. 2, ra2 (2009). References 57 and 58 genetically validate mTOR as a selective cancer target in prostate cancer.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Evangelisti, C. et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia 25, 781–791 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Janes, M. R. et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Med. 16, 205–213 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rodrik-Outmezguine, V. S. et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1, 248–259 (2011). This is a detailed analysis of the feedback effects of mTOR kinase inhibitors and the role of FOXO transcription factors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ballif, B. A. et al. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc. Natl Acad. Sci. USA 102, 667–672 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Ma, L. et al. Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res. 67, 7106–7112 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Tabernero, J. et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J. Clin. Oncol. 26, 1603–1610 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. She, Q. B. et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18, 39–51 (2010). This paper provides evidence for the convergence of PI3K–AKT and RAS–ERK signals at the level of 4EBPs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, X. et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol. Cell. Biol. 27, 7405–7413 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lee, T., Yao, G., Nevins, J. & You, L. Sensing and integration of Erk and PI3K signals by Myc. PLoS Computat. Biol. 4, e1000013 (2008).

    Article  CAS  Google Scholar 

  70. Brachmann, S. M. et al. Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations. Mol. Cancer Ther. 11, 1747–1757 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Advani, R. H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol. 31, 88–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Corcoran, R. B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. 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, 6013–6023 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gupta, S. et al. Binding of Ras to phosphoinositide 3-kinase p110α is required for Ras-driven tumorigenesis in mice. Cell 129, 957–968 (2007). This knock-in mouse defined a role for p110α in RAS transformation.

    Article  CAS  PubMed  Google Scholar 

  77. Nacht, M. et al. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα. J. Med. Chem. 56, 712–721 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Lee, J. H. et al. De novo somatic mutations in components of the PI3K–AKT3–mTOR pathway cause hemimegalencephaly. Nature Genet. 44, 941–945 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Lindhurst, M. J. et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nature Genet. 44, 928–933 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. 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, 934–940 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Angulo, I. et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342, 866–871 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lucas, C. L. et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nature Immunol. http://dx.doi.org/10.1038/ni.2771 (2013). References 81 and 82 identify human immunodeficiency patients with gain-of-function mutations affecting p110δ.

  83. Jia, S. et al. Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature 454, 776–779 (2008). This paper provides the first genetic evidence for p110β function in tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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, 97–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Wee, S. et al. PTEN-deficient cancers depend on PIK3CB. Proc. Natl Acad. Sci. USA 105, 13057–13062 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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, 151–159 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Iyengar, S. et al. P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood 121, 2274–2284 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu, N. et al. BAY 80–6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol. Cancer Ther. 12, 2319–2330 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Subramaniam, P. S. et al. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell 21, 459–472 (2012). This paper provides proof of concept for the dual targeting of p110γ and p110δ in T cell leukaemia.

    Article  CAS  PubMed  Google Scholar 

  90. Winkler, D. G. et al. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem. Biol. 20, 1364–1374 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Boyle, D. L. Kim, H. R., Topolewski, K., Bartok, B. & Firestein, G. S. Novel dual phosphoinositide 3-kinase-δ,γ inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J. Pharmacol. Exp. Ther. http://dx.doi.org/10.1124/jpet.113.205955 (2013).

  92. 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, 715–727 (2011). This study shows that p110γ activity in myeloid cells acts downstream of diverse receptors and promotes the formation of solid tumours even though the isoform is not expressed in cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. So, L. et al. Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function. J. Biol. Chem. 288, 5718–5731 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Brunn, G. J. et al. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 15, 5256–5267 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gharbi, S. I. et al. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem. J. 404, 15–21 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733–747 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kharas, M. G. et al. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J. Clin. Invest. 118, 3038–3050 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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 study demonstrates that mTORC1 preserves survival in PIK3CA -mutant cells treated with p110α inhibitors.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Yuan, R., Kay, A., Berg, W. J. & Lebwohl, D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J. Hematol. Oncol. 2, 45 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Sankhala, K. et al. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol. 4, 135–142 (2009).

    Article  PubMed  Google Scholar 

  102. Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Rev. Drug Discov. 10, 868–880 (2011).

    Article  CAS  Google Scholar 

  103. Janes, M. R. & Fruman, D. A. Targeting TOR dependence in cancer. Oncotarget 1, 69–76 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Gentzler, R. D., Altman, J. K. & Platanias, L. C. An overview of the mTOR pathway as a target in cancer therapy. Expert Opin. Ther. Targets 16, 481–489 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Chresta, C. M. et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 70, 288–298 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Yu, K. et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 70, 621–631 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Garcia-Garcia, C. et al. Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin. Cancer Res. 18, 2603–2612 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Alain, T., Sonenberg, N. & Topisirovic, I. mTOR inhibitor efficacy is determined by the eIF4E/4E-BP ratio. Oncotarget 3, 1491–1492 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Martineau, Y. et al. Pancreatic tumours escape from translational control through 4E-BP1 loss. Oncogene http://dx.doi.org/10.1038/onc.2013.100 (2013).

  110. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012). This cinical study establishes the combination of rapalogues with anti-oestrogen therapy in breast cancer.

    Article  CAS  PubMed  Google Scholar 

  111. Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358, 140–151 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Krueger, D. A. et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80, 574–580 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012). This paper demonstrates that genome sequencing of rare responders can identify predictive biomarkers for rapalogue sensitivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Panchaud, N., Peli-Gulli, M. P. & De Virgilio, C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6, ra42 (2013).

    Article  PubMed  CAS  Google Scholar 

  116. Corcoran, R. B. et al. TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma. Sci. Transl. Med. 5, 196ra98 (2013).

    Article  PubMed  CAS  Google Scholar 

  117. Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nature Rev. Immunol. 9, 324–337 (2009).

    Article  CAS  Google Scholar 

  119. Zeng, H. & Chi, H. mTOR and lymphocyte metabolism. Curr. Opin. Immunol. 25, 347–355 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nature Immunol. 12, 295–303 (2011). This is an informative dissection of the functions of mTORC1 and mTORC2 in T cell differentiation, which were determined using genetic and pharmacological approaches.

    Article  CAS  Google Scholar 

  123. Katholnig, K., Linke, M., Pham, H., Hengstschlager, M. & Weichhart, T. Immune responses of macrophages and dendritic cells regulated by mTOR signalling. Biochem. Soc. Trans. 41, 927–933 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Procaccini, C. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genet. 7, 619 (2006).

    Article  CAS  Google Scholar 

  127. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Bellacosa, A., Testa, J. R., Staal, S. P. & Tsichlis, P. N. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254, 274–277 (1991).

    Article  CAS  PubMed  Google Scholar 

  129. Rhodes, N. et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 68, 2366–2374 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Yap, T. A. et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J. Clin. Oncol. 29, 4688–4695 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Pal, S. K., Reckamp, K., Yu, H. & Figlin, R. A. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin. Investigat. Drugs 19, 1355–1366 (2010).

    Article  CAS  Google Scholar 

  133. Lin, J. et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin. Cancer Res. 19, 1760–1772 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Vakana, E., Altman, J. K. & Platanias, L. C. Targeting AMPK in the treatment of malignancies. J. Cell. Biochem. 113, 404–409 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Lindqvist, L. & Pelletier, J. Inhibitors of translation initiation as cancer therapeutics. Future Med. Chem. 1, 1709–1722 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Moerke, N. J. et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 128, 257–267 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Li, S., Brown, M. S. & Goldstein, J. L. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc. Natl Acad. Sci. USA 107, 3441–3446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Okuzumi, T. et al. Inhibitor hijacking of Akt activation. Nature Chem. Biol. 5, 484–493 (2009).

    Article  CAS  Google Scholar 

  139. Pearce, L. R. et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem. J. 431, 245–255 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Tandon, P. et al. Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. Proc. Natl Acad. Sci. USA 108, 2361–2365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Merkel, A. L., Meggers, E. & Ocker, M. PIM1 kinase as a target for cancer therapy. Expert Opin. Investigat. Drugs 21, 425–436 (2012).

    Article  CAS  Google Scholar 

  142. Yang, J. et al. eIF4B phosphorylation by Pim kinases plays a critical role in cellular transformation by Abl oncogenes. Cancer Res. 73, 4898–4908 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Wendel, H. G. et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 21, 3232–3237 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zimmermann, G. et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638–642 (2013). References 144 and 145 identify promising new approaches to target oncogenic RAS.

    Article  CAS  PubMed  Google Scholar 

  146. Chakrabarty, A. et al. Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. Cancer Res. 73, 1190–1200 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Donev, I. S. et al. Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer. Clin. Cancer Res. 17, 2260–2269 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Rexer, B. N. & Arteaga, C. L. Optimal targeting of HER2–PI3K signaling in breast cancer: mechanistic insights and clinical implications. Cancer Res. 73, 3817–3820 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Floris, G. et al. A potent combination of the novel PI3K inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal. Clin. Cancer Res. 19, 620–630 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Young, C. D. et al. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression or signaling. Cancer Res. 73, 4075–4085 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fiskus, W. et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol. Cancer Ther. 12, 577–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Vogt, P. K. & Hart, J. R. PI3K and STAT3: a new alliance. Cancer Discov. 1, 481–486 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065–3074 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Kinkade, C. W. et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J. Clin. Invest. 118, 3051–3064 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Zmajkovicova, K. et al. MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance. Mol. Cell 50, 43–55 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Posch, C. et al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc. Natl Acad. Sci. USA 110, 4015–4020 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bean, G. R. et al. PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci. Signal. 6, ra20 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Liu, Y. et al. Rapamycin induces Bad phosphorylation in association with its resistance to human lung cancer cells. Mol. Cancer Ther. 11, 45–56 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Ellenrieder, V. et al. Transforming growth factor β1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 61, 4222–4228 (2001).

    CAS  PubMed  Google Scholar 

  160. Mulholland, D. J. et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 72, 1878–1889 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shimizu, T. et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin. Cancer Res. 18, 2316–2325 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Coffee, E. M. et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAFV600E colorectal cancer. Clin. Cancer Res. 19, 2688–2698 (2013).

    Article  CAS  PubMed  Google Scholar 

  164. Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Mertz, J. A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669–16674 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Dominguez-Sola, D. & Dalla-Favera, R. Burkitt lymphoma: much more than MYC. Cancer Cell 22, 141–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  169. Sander, S. et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell 22, 167–179 (2012). This paper establishes an animal model for Burkitt's lymphoma, which requires both MYC and active PI3K.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Schmitz, R. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116–120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Pourdehnad, M. et al. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl Acad. Sci. USA 110, 11988–11993 (2013). This paper provides evidence that MYC-driven lymphoma is addicted to mTOR activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Grabher, C., von Boehmer, H. & Look, A. T. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nature Rev. Cancer 6, 347–359 (2006).

    Article  CAS  Google Scholar 

  173. Guo, D., Teng, Q. & Ji, C. NOTCH and phosphatidylinositide 3-kinase/phosphatase and tensin homolog deleted on chromosome ten/AKT/mammalian target of rapamycin (mTOR) signaling in T-cell development and T-cell acute lymphoblastic leukemia. Leuk. Lymphoma 52, 1200–1210 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Shanware, N. P., Bray, K. & Abraham, R. T. The PI3K, metabolic, and autophagy networks: interactive partners in cellular health and disease. Annu. Rev. Pharmacol. Toxicol. 53, 89–106 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Carayol, N. et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc. Natl Acad. Sci. USA 107, 12469–12474 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Fan, Q. W. et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci. Signal. 3, ra81 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kao, G. D., Jiang, Z., Fernandes, A. M., Gupta, A. K. & Maity, A. Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J. Biol. Chem. 282, 21206–21212 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. Kumar, A., Fernandez-Capetillo, O. & Carrera, A. C. Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair. Proc. Natl Acad. Sci. USA 107, 7491–7496 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 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, 1036–1047 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Juvekar, A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2, 1048–1063 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bassi, C. et al. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science 341, 395–399 (2013). This paper identifies the novel sumoylation and nuclear function of PTEN.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lempiainen, H. & Halazonetis, T. D. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J. 28, 3067–3073 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Munck, J. M. et al. Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K. Mol. Cancer Ther. 11, 1789–1798 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Khalaileh, A. et al. Phosphorylation of ribosomal protein S6 attenuates DNA damage and tumor suppression during development of pancreatic cancer. Cancer Res. 73, 1811–1820 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Shen, C. et al. Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double strand breaks. Cancer Res. 73, 3393–3401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Guo, F. et al. mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells. Leukemia 27, 2040–2046 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Miller, T. W., Balko, J. M. & Arteaga, C. L. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J. Clin. Oncol. 29, 4452–4461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

    Article  CAS  PubMed  Google Scholar 

  189. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Ammirante, M., Luo, J. L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Davids, M. S. & Letai, A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J. Clin. Oncol. 30, 3127–3135 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Letai, A. et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2, 183–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  193. Certo, M. et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9, 351–365 (2006).

    Article  CAS  PubMed  Google Scholar 

  194. Coloff, J. L. et al. Akt-dependent glucose metabolism promotes mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition. Cancer Res. 71, 5204–5213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Davids, M. S. et al. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood 120, 3501–3509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. 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, 1340–1351 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Hoellenriegel, J. et al. The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 118, 3603–3612 (2011). This study provides a mechanism for the efficacy of GS-1101 and includes pharmacodynamic data from clinical studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Kalos, M. & June, C. H. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49–60 (2013).

    Article  CAS  PubMed  Google Scholar 

  200. Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nature Rev. Cancer 12, 237–251 (2012).

    Article  CAS  Google Scholar 

  201. Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  202. Fruman, D. A. & Bismuth, G. Fine tuning the immune response with PI3K. Immunol. Rev. 228, 253–272 (2009).

    Article  CAS  PubMed  Google Scholar 

  203. Okkenhaug, K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu. Rev. Immunol. 31, 675–704 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Jiang, Q. et al. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res. 71, 4074–4084 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Li, Q. et al. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 34, 541–553 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Marshall, N. A. et al. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 72, 581–591 (2012). This paper shows that PI3K inhibitors can enhance the adjuvant activity of Toll-like receptor agonists to improve dendritic cell-based tumour vaccines in mice.

    Article  CAS  PubMed  Google Scholar 

  207. Yao, E. et al. Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin. Cancer Res. 15, 4147–4156 (2009).

    Article  CAS  PubMed  Google Scholar 

  208. Mao, M. et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 19, 657–667 (2013).

    Article  CAS  PubMed  Google Scholar 

  209. Paraiso, K. H. et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 71, 2750–2760 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Nardella, C., Lunardi, A., Patnaik, A., Cantley, L. C. & Pandolfi, P. P. The APL paradigm and the “co-clinical trial” project. Cancer Discov. 1, 108–116 (2011).

    Article  PubMed  Google Scholar 

  211. Suire, S. et al. Gβγs and the Ras binding domain of p110γ are both important regulators of PI(3)Kγ signalling in neutrophils. Nature Cell Biol. 8, 1303–1309 (2006).

    Article  CAS  PubMed  Google Scholar 

  212. Delgado, P. et al. Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nature Immunol. 10, 880–888 (2009).

    Article  CAS  Google Scholar 

  213. 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, 4943–4954 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Durand, C. A. et al. Phosphoinositide 3-kinase p110δ regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses. J. Immunol. 183, 5673–5684 (2009).

    Article  CAS  PubMed  Google Scholar 

  216. Reif, K. et al. Cutting edge: differential roles for phosphoinositide 3-kinases, 110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173, 2236–2240 (2004).

    Article  CAS  PubMed  Google Scholar 

  217. Puri, K. D. & Gold, M. R. Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies. Frontiers Immunol. 3, 256 (2012).

    Article  Google Scholar 

  218. Ghosh, B. et al. Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation. ACS Chem. Biol. 4, 367–377 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Knauf, U., Tschopp, C. & Gram, H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol. Cell. Biol. 21, 5500–5511 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Lim, S. et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc. Natl Acad. Sci. USA 110, E2298–E2307 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Konicek, B. W. et al. Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. Cancer Res. 71, 1849–1857 (2011).

    Article  CAS  PubMed  Google Scholar 

  222. Lin, Y. W. et al. A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood 115, 824–833 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Blanco-Aparicio, C. et al. Pim 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition. Cancer Lett. 300, 145–153 (2011).

    Article  CAS  PubMed  Google Scholar 

  224. Chen, L. S., Redkar, S., Bearss, D., Wierda, W. G. & Gandhi, V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood 114, 4150–4157 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Song, J. H. & Kraft, A. S. Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737. Cancer Res. 72, 294–303 (2012).

    Article  CAS  PubMed  Google Scholar 

  226. Pogacic, V. et al. Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity. Cancer Res. 67, 6916–6924 (2007).

    Article  CAS  PubMed  Google Scholar 

  227. Rommel, C. et al. Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 286, 1738–1741 (1999).

    Article  CAS  PubMed  Google Scholar 

  228. Zimmermann, S. & Moelling, K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286, 1741–1744 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank J. Oliner for critical review of the manuscript, and B. Vanhaesebroeck for sharing unpublished results. Research on PI3K and mTOR in David Fruman's laboratory is supported by US National Institutes of Health (NIH) grants CA158383 and AI099656, and the Cancer Center Support Grant P30CA62203 to University of California, Irvine (UC Irvine).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to David A. Fruman or Christian Rommel.

Ethics declarations

Competing interests

C.R. is an employee of Amgen Inc., a biopharmaceutical company discovering, developing and commercializing human therapeutics.

Related links

PowerPoint slides

Supplementary information

Glossary

Phosphoinositide 3-kinase

(PI3K). A lipid kinase that produces phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3; also known as PIP3), which is a key signalling lipid.

AKT

A serine/threonine kinase whose activation is dependent on phosphoinositide 3-kinase.

Mammalian target of rapamycin

(mTOR). A serine/threonine kinase that functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTORC2.

PIK3CA

The human gene encoding the p110a catalytic isoform of phosphoinositide 3-kinase (PI3K). Gain-of-function mutations in PIK3CA are frequent in cancer.

Phosphatase and tensin homolog

(PTEN). A lipid 3-phosphatase that opposes phosphoinositide 3-kinase (PI3K) signalling and is often disabled in cancer.

RAS

A family of small GTPases that are often mutated in cancer and activate phosphoinositide 3-kinase (PI3K) and other oncogenic signals.

Rapalogues

Structural analogues of rapamycin that inhibit mammalian target of rapamycin (mTOR) but have altered pharmacological properties.

Pan-PI3K inhibitors

Molecules that inhibit all class I phosphoinositide 3-kinase (PI3K) enzymes but are selective relative to other lipid and protein kinases.

Basket trials

Clinical trials that enrol patients with tumours of diverse tissue and histological origin, but with a shared genetic signature (in this case, PI3K catalytic isoform p110α (PIK3CA)-mutant tumours).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fruman, D., Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13, 140–156 (2014). https://doi.org/10.1038/nrd4204

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4204

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer