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  • Review Article
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Targeting the PI3K pathway in cancer: are we making headway?

Nature Reviews Clinical Oncology volume 15, pages 273–291 (2018)Cite this article

Subjects

Key Points

  • The PI3K–AKT–mTOR signalling pathway, which controls multiple cellular processes including metabolism, motility, proliferation, growth, and survival, is one of the most frequently dysregulated pathways in human cancers.

  • The PI3K–AKT–mTOR pathway can be aberrantly activated by multiple factors, including diverse oncogenic genomic alterations in PIK3CA, PIK3R1, PTEN, AKT, TSC1, TSC2, LKB1, MTOR, and other critical genes, which can serve as targets for anticancer therapy.

  • More than 40 inhibitors of the PI3K–AKT–mTOR signalling pathway have reached different stages of clinical development, but few — temsirolimus, everolimus, idelalisib, and copanlisib — have been approved for clinical use.

  • Limited single-agent activity, problematic levels of toxicity, and a lack of predictive biomarkers for treatment selection have all been major barriers to the clinical translation of agents that target components of the PI3K–AKT–mTOR pathway.

  • Novel compounds and dosing schedules that have fewer off-target effects need to be developed; efforts to identify biomarkers associated with clinical activity also need to be expanded beyond PIK3CA or PTEN alterations.

  • Finally, as demonstrated in patients with metastatic hormone-receptor-positive breast cancer, combination strategies might open viable paths to advancing PI3K–AKT–mTOR inhibitors from clinical studies to new standard-of-care treatments.

Abstract

The PI3K–AKT–mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive. Nevertheless, the mTOR inhibitors temsirolimus and everolimus and the PI3K inhibitors idelalisib and copanlisib have been approved by the FDA for clinical use in the treatment of a number of different cancers. Novel compounds with greater potency and selectivity, as well as improved therapeutic indices owing to reduced risks of toxicity, are clearly required. In addition, biomarkers that are predictive of a response, such as PIK3CA mutations for inhibitors of the PI3K catalytic subunit α isoform, must be identified and analytically and clinically validated. Finally, considering that oncogenic activation of the PI3K–AKT–mTOR pathway often occurs alongside pro-tumorigenic aberrations in other signalling networks, rational combinations are also needed to optimize the effectiveness of treatment. Herein, we review the current experience with anticancer therapies that target the PI3K–AKT–mTOR pathway.

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Figure 1: Intracellular signalling via the PI3K–AKT–mTOR pathway.
Figure 2: Summary of pharmacological agents that target various components of the PI3K–AKT–mTOR pathway.
Figure 3: Pan-PI3K inhibitors.
Figure 4: Dual pan-PI3K and mTORC1–mTORC2 inhibitors.
Figure 5: Isoform-specific PI3K inhibitors.
Figure 6: AKT inhibitors.

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References

  1. Polivka, J. Jr & Janku, F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 142, 164–175 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627–644 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fruman, D. A. & Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. Drug Discov. 13, 140–156 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Janku, F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat. Rev. 59, 93–101 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Yap, T. A., Bjerke, L., Clarke, P. A. & Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharmacol. 23, 98–107 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thorpe, L. M., Yuzugullu, H. & Zhao, J. J. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 15, 7–24 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Janku, F. et al. PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol. Cancer Ther. 10, 558–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Janku, F. et al. Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell Rep. 6, 377–387 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hyman, D. M. et al. AKT inhibition in solid tumors with AKT1 mutations. J. Clin. Oncol. 35, 2251–2259 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kwiatkowski, D. J. et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 22, 2445–2452 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wagle, N. et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 371, 1426–1433 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Krueger, D. A. et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363, 1801–1811 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Cheng, H. et al. RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov. 5, 1262–1270 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grabiner, B. C. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4, 554–563 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Moulder, S. et al. Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer. Ann. Oncol. 26, 1346–1352 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Moulder, S. et al. Responses to liposomal doxorubicin, bevacizumab, and temsirolimus in metaplastic carcinoma of the breast: biologic rationale and implications for stem-cell research in breast cancer. J. Clin. Oncol. 29, e572–e575 (2011).

    Article  PubMed  Google Scholar 

  19. Ihle, N. T. et al. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res. 69, 143–150 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Di Nicolantonio, F. et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Invest. 120, 2858–2866 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351–1356 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Janku, F. et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J. Clin. Oncol. 30, 777–782 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Janku, F. et al. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res. 73, 276–284 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Mayer, I. A. et al. A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clin. Cancer Res. 23, 26–34 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Baselga, J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Janku, F., McConkey, D. J., Hong, D. S. & Kurzrock, R. Autophagy as a target for anticancer therapy. Nat. Rev. Clin. Oncol. 8, 528–539 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Yao, J. C. et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bissler, J. J. et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381, 817–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Franz, D. N. et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381, 125–132 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 17, 917–927 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Yao, J. C. et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387, 968–977 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Demetri, G. D. et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J. Clin. Oncol. 31, 2485–2492 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Gonzalez-Angulo, A. M. et al. Weekly nab-rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. Clin. Cancer Res. 19, 5474–5484 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nat. Rev. Cancer 6, 729–734 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317–1322 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yu, Y. et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332, 1322–1326 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Banerji, U. et al. First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), 3004 (2012).

    Google Scholar 

  46. Schmid, P. et al. in San Antonio Breast Cancer Symposium GS2-07 (San Antonio, Texas, 2017).

    Google Scholar 

  47. Naing, A. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br. J. Cancer 107, 1093–1099 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ghobrial, I. M. et al. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenstrom's macroglobulinemia. Am. J. Hematol. 91, 400–405 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Infante, J. R. et al. A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies [abstract]. Mol. Cancer Ther. 12 (Suppl.), C252 (2013).

    Google Scholar 

  50. Bendell, J. C. et al. A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma. Cancer 121, 3481–3490 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Mateo, J. et al. A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. Br. J. Cancer 114, 889–896 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Baselga, J. et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 904–916 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Di Leo, A. et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 19, 87–100 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. Martin, M. et al. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2− advanced breast cancer (BELLE-4). Ann. Oncol. 28, 313–320 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Bendell, J. C. et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–290 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Bedard, P. L. et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin. Cancer Res. 21, 730–738 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Farley, J. et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 14, 134–140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Krop, I. E. et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 17, 811–821 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vuylsteke, P. et al. Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Ann. Oncol. 27, 2059–2066 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Shapiro, G. I. et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 20, 233–245 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Matulonis, U. et al. Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol. Oncol. 136, 246–253 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Tolaney, S. et al. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res. Treat. 149, 151–161 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Soria, J. C. et al. Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors. Oncologist 20, 245–246 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Brown, J. R. et al. Phase I trial of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma. Clin. Cancer Res. 21, 3160–3169 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Abramson, V. G. et al. Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors. Clin. Cancer Res. 23, 3520–3528 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Wheler, J. et al. Phase I dose-escalation study of pilaralisib (SAR245408, XL147) in combination with paclitaxel and carboplatin in patients with solid tumors. Oncologist 22, 377–e37 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Patnaik, A. et al. First-in-human phase I study of copanlisib (BAY 80–6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann. Oncol. 27, 1928–1940 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dreyling, M. et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J. Clin. Oncol. 35, 3898–3905 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Hong, D. S. et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 18, 4173–4182 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Bowles, D. W. et al. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br. J. Cancer 109, 1085–1092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yam, C. et al. A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600 mutant solid tumors. Clin. Cancer Res. 24, 22–32 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Levy, B. et al. A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer. J. Thorac Oncol. 9, 1031–1035 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Bowles, D. W. et al. A multicenter phase 1 study of PX-866 and cetuximab in patients with metastatic colorectal carcinoma or recurrent/metastatic squamous cell carcinoma of the head and neck. Invest. New Drugs 32, 1197–1203 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Jimeno, A. et al. A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Ann. Oncol. 26, 556–561 (2015).

    Article  CAS  PubMed  Google Scholar 

  76. Jimeno, A. et al. A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral Oncol. 51, 383–388 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pitz, M. W. et al. Phase II study of PX-866 in recurrent glioblastoma. Neuro Oncol. 17, 1270–1274 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Bowles, D. W. et al. A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with metastatic colorectal carcinoma. Clin. Colorectal Cancer 15, 337–344.e2 (2016).

    Article  PubMed  Google Scholar 

  79. Blagden, S. et al. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer. Clin. Cancer Res. 20, 5908–5917 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lockhart, A. C. et al. A first-in-human phase I study of ZSTK474, an oral pan-PI3K inhibitor, in patients with advanced solid malignancies [abstract]. Mol. Cancer Ther. 12, B271 (2013).

    Google Scholar 

  81. Mahadevan, D. et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur. J. Cancer 48, 3319–3327 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Juric, D. et al. A first-in-human, phase I, dose-escalation study of TAK-117, a selective PI3Kα isoform inhibitor, in patients with advanced solid malignancies. Clin. Cancer Res. 23, 5015–5023 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Markman, B. et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann. Oncol. 23, 2399–2408 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Bendell, J. C. et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest. New Drugs 33, 463–471 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Carlo, M. I. et al. A phase Ib study of BEZ235, a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in patients with advanced renal cell carcinoma. Oncologist 21, 787–788 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Massard, C. et al. Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer. Eur. J. Cancer 76, 36–44 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Dolly, S. O. et al. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 22, 2874–2884 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Makker, V. et al. A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer 122, 3519–3528 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Powles, T. et al. Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 34, 1660–1668 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shapiro, G. I. et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin. Cancer Res. 21, 1888–1895 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Britten, C. D. et al. Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest. New Drugs 32, 510–517 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Moore, K. N. et al. A phase I, first-in-human dose study of the dual PI3K/mTOR inhibitor LY3023414 (LY) in patients (pts) with advanced cancer. J. Clin. Oncol. 33, 11075–11075 (2015).

    Article  Google Scholar 

  93. Kristeleit, R. S. et al. A phase 1 first-in-human (FIH) dose-escalation (DE) study of the oral dual PI3K/mTOR inhibitor PQR309 in patients (pts) with advanced solid tumors: final DE results [abstract]. J. Clin. Oncol. 33 (Suppl.), 2592 (2015).

    Article  Google Scholar 

  94. Sambandam, V. et al. Identification of NOTCH1 inactivating mutation as a therapeutic vulnerability to PI3K/mTOR pathway inhibition in head and neck squamous cell carcinoma (HNSCC) [abstract]. Cancer Res. 77 (Suppl.), 2992 (2017).

    Google Scholar 

  95. Okkenhaug, K. & Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 3, 317–330 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Juric, D. et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature 518, 240–244 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Juric, D. et al. Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J. Clin. Oncol. https://doi.org/10.1200/JCO.2017.72.7107 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Janku, F. et al. Phase I study of the PI3K alpha inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2− locally advanced or metastatic breast cancer [abstract]. Cancer Res. 75 (Suppl.), PD5-5 (2015).

    Google Scholar 

  99. 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 

  100. Bosch, A. et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl Med. 7, 283ra51 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. van Geel, R. et al. A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov. 7, 610–619 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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 

  103. 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 

  104. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Juric, D. et al. Phase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov. 7, 704–715 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Baselga, J. et al. SANDPIPER: phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors [abstract]. J. Clin. Oncol. 35 (Suppl.), TPS1119 (2017).

    Article  Google Scholar 

  107. Saura, C. et al. Primary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC) [abstract]. Ann. Oncol. 28 (Suppl.), LBA9 (2017).

    Google Scholar 

  108. Thompson, S. K. et al. ASN003, a unique B-RAF inhibitor with additional selective activity against PI3K and mTOR kinases, shows strong antitumor activity in multiple xenograft models [abstract]. Mol. Cancer Ther. 14 (Suppl. 2), B100 (2015).

    Google Scholar 

  109. Jia, S. et al. Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature 454, 776–779 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ni, J. et al. Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. Cancer Discov. 2, 425–433 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mateo, J. et al. A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 23, 5981–5992 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Hansen, A. R. et al. A first in human phase I study of AZD8186, a potent and selective inhibitor of PI3K in patients with advanced solid tumours as monotherapy and in combination with the dual mTORC1/2 inhibitor vistusertib or abiraterone acetate [abstract]. J. Clin. Oncol. 35 (Suppl.), 2570 (2017).

    Article  Google Scholar 

  113. Bédard, P. L. et al. First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in patients with advanced solid tumors. Cancer 124, 315–324 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Randis, T. M., Puri, K. D., Zhou, H. & Diacovo, T. G. Role of PI3Kδ and PI3Kγ in inflammatory arthritis and tissue localization of neutrophils. Eur. J. Immunol. 38, 1215–1224 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Barbi, J. et al. PI3Kgamma (PI3Kγ) is essential for efficient induction of CXCR3 on activated T cells. Blood 112, 3048–3051 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443–447 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tolcher, A. et al. IPI-549-01 — a phase 1/1b, first-in-human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with nivolumab in patients with advanced solid tumors [abstract]. Cancer Res. 77 (Suppl.), CT089 (2017).

    Google Scholar 

  118. Lampson, B. L. et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 128, 195–203 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Barr, P. M. et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood 127, 2411–2415 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Miller, B. W. et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin. Cancer Res. 21, 1525–1529 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Zelenetz, A. D. et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 18, 297–311 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. US Food and Drug Administration. FDA alerts healthcare professionals about clinical trials with Zydelig (idelalisib) in combination with other cancer medicines [online]. https://www.fda.gov/Drugs/DrugSafety/ucm490618.htm (2016).

  123. O'Brien, S. et al. Duvelisib (IPI-145), a PI3K-δ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. Blood 124, 3334–3334 (2014).

    Google Scholar 

  124. Porcu, P. et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, in patients previously treated with ibrutinib. Blood 124, 3335–3335 (2014).

    Article  Google Scholar 

  125. Flinn, I. et al. A phase 1 evaluation of duvelisib (IPI-145), a PI3K-δ,γ inhibitor, in patients with relapsed/refractory iNHL. Blood 124, 802–802 (2014).

    Google Scholar 

  126. Horwitz, S. M. et al. Duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Blood 124, 803–803 (2014).

    Article  CAS  Google Scholar 

  127. Flinn, I. et al. An open-label, phase Ib study of duvelisib (IPI-145) in combination with bendamustine, rituximab or bendamustine/rituximab in select subjects with lymphoma or chronic lymphocytic leukemia. Blood 124, 4422–4422 (2014).

    Google Scholar 

  128. Glenn, M. et al. First-in-human study of AMG 319, a highly selective, small molecule inhibitor of PI3Kδ, in adult patients with relapsed or refractory lymphoid malignancies. Blood 122, 678–678 (2013).

    Google Scholar 

  129. 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 

  130. Rugo, H. S. et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N. Engl. J. Med. 375, 23–34 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Park, J. W. et al. Adaptive randomization of neratinib in early breast cancer. N. Engl. J. Med. 375, 11–22 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tripathy, D. et al. Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206: graduation results from the I-SPY 2 trial [abstract]. J. Clin. Oncol. 33, 524 (2015).

    Article  Google Scholar 

  133. Papadimitrakopoulou, V. et al. The BATTLE-2 study: a biomarker-integrated targeted therapy study in previously treated patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 34, 3638–3647 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sangai, T. et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin. Cancer Res. 18, 5816–5828 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Gonzalez-Angulo, A. M. et al. SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J. Natl Cancer Inst. 107, dju493 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yap, T. A. et al. Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clin. Cancer Res. 20, 5672–5685 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Tolcher, A. et al. Results from a phase 1 study of ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma [abstract]. Eur. J. Cancer 51 (Suppl. 3), 338 (2015).

    Google Scholar 

  138. Yu, Y. et al. Targeting AKT1-E17K and the PI3K/AKT pathway with an allosteric AKT inhibitor, ARQ 092. PLoS ONE 10, e0140479 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Politz, O. et al. BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models. Int. J. Cancer 140, 449–459 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. Burris, H. A. et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study [abstract]. J. Clin. Oncol. 29 (Suppl.), 3003 (2011).

    Article  Google Scholar 

  141. Saura, C. et al. A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov. 7, 102–113 (2017).

    Article  CAS  PubMed  Google Scholar 

  142. Kim, S. B. et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 18, 1360–1372 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Banerji, U. et al. A phase 1 open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-2260 (2017).

    Article  CAS  PubMed  Google Scholar 

  144. Banerji, U. et al. A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in PIK3CA mutant breast and gynecological cancers [abstract]. J. Clin. Oncol. 33 (Suppl.), 2500 (2015).

    Article  Google Scholar 

  145. Tsimberidou, A. M. et al. A first in human, dose escalation trial of MSC2363318A — a dual p70S6K/Akt inhibitor, for patients with advanced malignancies [abstract]. Ann. Oncol. 26 (Suppl. 2), P5.01 (2015).

    Google Scholar 

  146. Janku, F. et al. PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. PLoS ONE 6, e22769 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ganesan, P. et al. Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations. Mol. Cancer Ther. 12, 2857–2863 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dienstmann, R. et al. Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase 1 clinical trials. Mol. Cancer Ther. 11, 2062–2071 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. McGranahan, N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl Med. 7, 283ra54 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yates, L. R. et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat. Med. 21, 751–759 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work of the authors has been supported by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, by the US National Institutes of Health (NIH) through the National Center for Advancing Translational Sciences (grant UL1 TR000371), and by an MD Anderson Cancer Center Support Grant (P30 CA016672). The authors thank J. Munch of the MD Anderson Department of Scientific Publications for editing the manuscript before submission.

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  1. Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Filip Janku, Timothy A. Yap & Funda Meric-Bernstam

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F.J. researched data for the article. All authors contributed to discussions of content and to writing, review, and editing of the manuscript.

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Correspondence to Filip Janku.

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Competing interests

F.J. has received research support from Genentech, Novartis, and Piqur and has served on scientific advisory boards for Novartis. T.A.Y. has been a member of the scientific advisory boards of AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, EMD Serono, Ignyta, and Pfizer, has received research funding from AstraZeneca, Clearbridge BioMedics, and Vertex, and has received travel support from AstraZeneca, Bristol-Myers Squibb, EMD Serono, Janssen-Cilag, MSD Oncology, and Vertex. F.M.-B. has received research funding from Aileron, AstraZeneca, Bayer, Calithera, Curis, CytomX, Debiopharm, Effective Pharmaceuticals, Genentech, Jounce, Novartis, Pfizer, PUMA, Taiho, and Zymeworks and has served on advisory boards for ClearLight Diagnostics, Darwin Health, GRAIL, and Pieris.

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Janku, F., Yap, T. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway?. Nat Rev Clin Oncol 15, 273–291 (2018). https://doi.org/10.1038/nrclinonc.2018.28

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