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.

Development of PI3K inhibitors: lessons learned from early clinical trials

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents—whether observed sequelae could be mechanism-based or off-target effects—and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.

Key Points

  • Agents targeting different components of the PI3K/AKT/mTOR pathway have been shown to be safe and well tolerated

  • These agents inhibit the PI3K/AKT/mTOR pathway at recommended doses, and are effective in multiple tumour types

  • No clear correlation among tumour type, genotype and sensitivity to inhibitors of the PI3K/AKT/mTOR pathway has emerged in initial clinical trials of second-generation inhibitors

  • Some unsolved questions in the late development of inhibitors of the PI3K/AKT/mTOR pathway might benefit from a systems biology approach and from biomarker-driven studies

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Signalling of the PI3K/AKT/mTOR pathway and relevant drugs that target each of the components of the pathway.
Figure 2: Distribution of ongoing clinical trials depending on the class of agent or treatment strategy.

References

  1. 1

    Courtney, K. D., Corcoran, R. B. & Engelman, J. A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 28, 1075–1083 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Chen, Y., Wang, B. C. & Xiao, Y. PI3K: a potential therapeutic target for cancer. J. Cell. Physiol. 227, 2818–2821 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Motzer, R. J. et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116, 4256–4265 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8

    Brana, I. et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3030 (2010).

    Article  Google Scholar 

  9. 9

    Edelman, G. et al. A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced malignancies [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3004 (2010).

    Article  Google Scholar 

  10. 10

    Furman, R. R. et al. Interim results from a phase I study of CAL-101, a selective oral inhibitor of phosphatidylinositol 3-kinase p110d isoform, in patients with relapsed or refractory hematologic malignancies. J. Clin. Oncol. 28 (15 Suppl.), a3032 (2010).

    Article  Google Scholar 

  11. 11

    Moreno Garcia, V. et al. A phase I study evaluating GDC-0941, an oral phosphoinositide-3 kinase (PI3K) inhibitor, in patients with advanced solid tumors or multiple myeloma. J. Clin. Oncol. 29 (Suppl.), a3021 (2011).

    Article  Google Scholar 

  12. 12

    Wagner, A. et al. A first-in-human phase I study to evaluate GDC-0980, an oral PI3K/mTOR inhibitor, administered QD in patients with advanced solid tumors. J. Clin. Oncol. 29 (Suppl.) a3020 (2011).

    Article  Google Scholar 

  13. 13

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606–619 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18

    Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Zhao, L. & Vogt, P. K. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl Acad. Sci. USA 105, 2652–2657 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21

    Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Hess, G. et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 27, 3822–3829 (2009).

    CAS  Article  Google Scholar 

  24. 24

    O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Miller, T. W., Rexer, B. N., Garrett, J. T. & Arteaga, C. L. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 13, 224 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Bachelot, T. et al. TAMRAD: A GINECO randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients with hormone-receptor positive, HER2 negative metastatic breast cancer with prior exposure to aromatase inhibitors [abstract]. Cancer Res. 70 (Suppl. 2), S1–S6 (2010).

    Google Scholar 

  27. 27

    Choo, A. Y., Yoon, S. O., Kim, S. G., Roux, P. P. & Blenis, J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl Acad. Sci. USA 105, 17414–17419 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Mothe-Satney, I., Yang, D., Fadden, P., Haystead, T. A. & Lawrence, J. C. Jr. Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression. Mol. Cell. Biol. 20, 3558–3567 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Jia, S., Roberts, T. M. & Zhao, J. J. Should individual PI3 kinase isoforms be targeted in cancer? Curr. Opin. Cell Biol. 21, 199–208 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31

    Tsai, J. et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl Acad. Sci. USA 105, 3041–3046 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Gungor, H. et al. Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer [abstract]. J. Clin. Oncol. 29 (Suppl.), a5064 (2011).

    Article  Google Scholar 

  33. 33

    Tabernero, J. et al. First-in-human phase I study evaluating the safety, pharmacokinetics (PK), and intratumor pharmacodynamics (PD) of the novel, oral, ATP-competitive Akt inhibitor GDC-0068 [abstract]. J. Clin. Oncol. 29 (Suppl.), a3022 (2011).

    Article  Google Scholar 

  34. 34

    Kondapaka, S. B., Singh, S. S., Dasmahapatra, G. P., Sausville, E. A. & Roy, K. K. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol. Cancer Ther. 2, 1093–1103 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Vasudevan, K. M. et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16, 21–32 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Burris, H. et al. First-in-human phase I study of the oral PI3K inhibitor BEZ235 in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3005 (2010).

    Article  Google Scholar 

  37. 37

    Dienstmann, R., Brana, I., Rodon, J. & Tabernero, J. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist 16, 1729–1740 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Van Cutsem, E. et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J. Clin. Oncol. 30, 2861–2868 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Busaidy, N. L. et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J. Clin. Oncol. 30, 2919–2928 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Foukas, L. C. et al. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125, 733–747 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Crean, S., Boyd, D. M., Sercus, B. & Lahn, M. Safety of multi-targeted kinase inhibitors as monotherapy treatment of cancer: a systematic review of the literature. Curr. Drug Saf. 4, 143–154 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  43. 43

    Biondo, A. et al. Phase I clinical trial of an allosteric AKT inhibitor, MK-2206, using a once weekly (QW) dose regimen in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 29 (Suppl.), a3037 (2011).

    Article  Google Scholar 

  44. 44

    Jimeno, A. et al. Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3089 (2010).

    Article  Google Scholar 

  45. 45

    Laird, A. D. et al. Evaluation of peripheral blood cells and hair as surrogate tissues for clinical trial pharmacodynamic assessment of XL147 and XL765, inhibitors of the PI3K signaling pathway [abstract 89]. Eur. J. Cancer Suppl. 6, 30 (2008).

    Article  Google Scholar 

  46. 46

    Williams, R. et al. The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother. Pharmacol. 58, 444–450 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Patnaik, A. et al. A first-in-human phase I study of intravenous PI3K inhibitor BAY 80-6946 in patients with advanced solid tumors: Results of dose-escalation phase [abstract]. J. Clin. Oncol. 29 (Suppl.), a3035 (2011).

    Article  Google Scholar 

  50. 50

    Ma, W. W. et al. [18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy. J. Clin. Oncol. 27, 2697–2704 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    McKinley, E. T. et al. 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer. Clin. Cancer Res. 17, 3332–3340 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Brana, I. & Siu, L. L. Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment. BMC Med. 10, 161 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Brachmann, S. M. et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc. Natl Acad. Sci. USA 106, 22299–22304 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    O'Brien, C. et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin. Cancer Res. 16, 3670–3683 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55

    Roper, J. et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS ONE 6, e25132 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Weigelt, B., Warne, P. H. & Downward, J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 30, 3222–3233 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Oliveira, M. et al. PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts) [abstract]. J. Clin. Oncol. 30 (Suppl.), a509 (2012).

    Google Scholar 

  59. 59

    Juric, D. et al. BYL719, a next generation PI3K alpha specific inhibitor: Preliminary safety, PK, and efficacy results from the first-in-human study [abstract]. Proc. 103rd Meeting of AACR CT-01 (2012).

  60. 60

    Hanrahan, A. J. & Solit, D. B. RAF/MEK dependence of KRAS-mutant pancreatic ductal adenocarcinomas. Cancer Discov. 2, 666–669 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Sos, M. L. et al. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc. Natl Acad. Sci. USA 106, 18351–18356 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Wallin, J. J. et al. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo. Clin. Cancer Res. 18, 3901–3911 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64

    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.), a3003 (2011).

    Article  Google Scholar 

  65. 65

    Edgar, K. A. et al. Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Res. 70, 1164–1172 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66

    Morrow, C. J., Gray, A. & Dive, C. Comparison of phosphatidylinositol-3-kinase signalling within a panel of human colorectal cancer cell lines with mutant or wild-type PIK3CA. FEBS Lett. 579, 5123–5128 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67

    Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Hanrahan, A. J. et al. Genomic complexity and AKT dependence in serous ovarian cancer. Cancer Discov. 2, 56–67 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Serra, V. et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30, 2547–2557 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Rodrik-Outmezguine, V. S. et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1, 248–259 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    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 

  73. 73

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74

    Liu, P. et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat. Med. 17, 1116–1120 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Muellner, M. K. et al. A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nat. Chem. Biol. 7, 787–793 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Tenbaum, S. P. et al. beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat. Med. 18, 892–901 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77

    Han, H. et al. A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors [abstract]. J. Clin. Oncol. 29 (Suppl.), a3028 (2011).

    Article  Google Scholar 

  78. 78

    Krop, I. E. et al. A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer [abstract]. J. Clin. Oncol. 30 (Suppl.), a508 (2012).

    Google Scholar 

  79. 79

    Yan, Y. et al. A first-in-human trial of GDC-0068: A novel, oral, ATP-competitive Akt inhibitor, demonstrates robust suppression of the Akt pathway in surrogate and tumor tissues [abstract]. Mol. Cancer Ther. 10 (Suppl.), B154 (2011).

    Article  Google Scholar 

  80. 80

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Bedard, P. et al. A phase lb, open-label, multicenter, dose-escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients (pts) with selected advanced solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), a3003 (2012).

    Google Scholar 

  82. 82

    Khan, K. H. et al. A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), e13599 (2012).

    Google Scholar 

  83. 83

    LoRusso, P. et al. A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), a2566 (2012).

    Google Scholar 

  84. 84

    Speranza, G. et al. Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC) [abstract]. 30 (Suppl.), a3529 (2012).

  85. 85

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  86. 86

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  87. 87

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  88. 88

    Crowder, R. J. et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 69, 3955–3962 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Mayer, I. et al. SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC) [abstract]. J. Clin. Oncol. 30 (Suppl.), a510 (2012).

    Google Scholar 

  90. 90

    Hafsi, S. et al. Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (review). Int. J. Oncol. 40, 639–644 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Bozulic, L., Surucu, B., Hynx, D. & Hemmings, B. A. PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol. Cell 30, 203–213 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92

    Hu, L., Hofmann, J., Lu, Y., Mills, G. B. & Jaffe, R. B. Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 62, 1087–1092 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Awasthi, N., Yen, P. L., Schwarz, M. A. & Schwarz, R. E. The efficacy of a novel, dual PI3K/mTOR inhibitor NVP-BEZ235 to enhance chemotherapy and antiangiogenic response in pancreatic cancer. J. Cell. Bio. 113, 784–791 (2012).

    CAS  Article  Google Scholar 

  94. 94

    Fekete, M., Santiskulvong, C., Eng, C. & Dorigo, O. Effect of PI3K/Akt pathway inhibition-mediated G1 arrest on chemosensitization in ovarian cancer cells. Anticancer Res. 32, 445–452 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Mallon, R. et al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin. Cancer Res. 17, 3193–3203 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96

    Besse, B. et al. A phase Ib study to evaluate the PI3-kinase inhibitor GDC-0941 with paclitaxel (P) and carboplatin (C), with and without bevacizumab (BEV), in patients with advanced non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 29 (Suppl.), a3044 (2011).

    Article  Google Scholar 

  97. 97

    Jimeno, A. et al. PX-866 and docetaxel in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), a3024 (2012).

    Google Scholar 

  98. 98

    Saura, C. et al. A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or mFOLFOX-6 (F) in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), a3021 (2012).

    Google Scholar 

  99. 99

    Arteaga, C. L. Clinical development of phosphatidylinositol-3 kinase pathway inhibitors. Curr. Top. Microbiol. Immunol. 347, 189–208 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Juric, D. & Baselga, J. Tumor genetic testing for patient selection in phase I clinical trials: the case of PI3K inhibitors. J. Clin. Oncol. 30, 765–766 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101

    Baselga, J. et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol. 27, 2630–2637 (2009).

    CAS  Article  Google Scholar 

  102. 102

    Bast, R. C. Jr & Mills, G. B. Dissecting “PI3Kness”: the complexity of personalized therapy for ovarian cancer. Cancer Discov. 2, 16–18 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Higgins, M. J. et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin. Cancer Res. 18, 3462–3469 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104

    Rodon, J. et al. Molecular prescreening to select patient population in early clinical trials. Nat. Rev. Clin. Oncol. 9, 359–366 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105

    Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  106. 106

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  107. 107

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  108. 108

    Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109

    Agoulnik, I. U., Hodgson, M. C., Bowden, W. A. & Ittmann, M. M. INPP4B: the new kid on the PI3K block. Oncotarget 2, 321–328 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110

    Omlin, A. G. et al. A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human study of the oral class I PI3K inhibitor CH5132799, in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), a3022 (2012).

    Google Scholar 

  111. 111

    Tan, D. S. et al. First-in-human phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma [abstract]. J. Clin. Oncol. 28 (Suppl.15), a3006 (2010).

    Article  Google Scholar 

  112. 112

    Banerji, U. et al. First results from a phase I trial of AZD8055, a dual mTORC1 and mTORC2 inhibitor [abstract]. J. Clin. Oncol. 29 (Suppl.), a3096 (2011).

    Article  Google Scholar 

  113. 113

    Shih, K. C. et al. Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers [abstract]. J. Clin. Oncol. 30 (Suppl.), a3006 (2012).

    Google Scholar 

  114. 114

    Tabernero, J. et al. A phase I, open label, dose escalation study of oral mammalian target of rapamycin inhibitor INK128 administered by intermittent dosing regimens in patients with advanced malignancies [abstract]. Cancer Res. 72 (Suppl. 1), CT-02 (2012).

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge José Baselga, Lew Cantley, and other members of the “Stand Up to Cancer Dream Team” Translational Research Grant for sharing their insights on targeting PI3K. In addition, Joann Aaron (The University of Texas MD Anderson Cancer Center) for editing this manuscript.

Author information

Affiliations

Authors

Contributions

All the authors researched the data for the manuscript, made a substantial contribution to discussion of content, wrote and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jordi Rodon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Development status of PI31/AKT/mTOR pathway inhibitors (DOC 132 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rodon, J., Dienstmann, R., Serra, V. et al. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10, 143–153 (2013). https://doi.org/10.1038/nrclinonc.2013.10

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing