The PI3K/AKT/mTOR pathway in breast cancer: Targets, trials and biomarkers

Therapeutic Advances in Medical Oncology

Volumn 6, Issue 4, 2014, Pages 154-166

  Paplomata, Elisavet ^a   O’regan, Ruth ^a  

^a EMORY UNIVERSITY   (United States)

Author keywords

Akt; breast cancer; endocrine resistance; everolimus; mammalian (or mechanistic) target of rapamycin; phosphatase and tensin homolog; phosphoinositide 3 kinase; PIK3CA

Indexed keywords

APOPTOSIS SIGNAL REGULATING KINASE 1; BIOLOGICAL MARKER; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B;

ANEMIA; BONE MARROW SUPPRESSION; BREAST CANCER; CANCER RESISTANCE; CLINICAL TRIAL (TOPIC); DEPRESSION; DIARRHEA; DYSPNEA; FATIGUE; GASTROINTESTINAL TOXICITY; GENE EXPRESSION; GENE MUTATION; HALLUCINATION; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; MOOD DISORDER; NAUSEA; ONCOGENE K RAS; ONCOGENE NEU; PNEUMONIA; PRIORITY JOURNAL; PROTEIN TARGETING; RASH; REVIEW; STOMATITIS; TREATMENT RESPONSE; VOMITING;

EID: 84904794527     PISSN: 17588340     EISSN: 17588359     Source Type: Journal    
DOI: 10.1177/1758834014530023     Document Type: Review

References (75)

1. Andre F. Campone M. O'Regan R. Manlius C. Massacesi C. Sahmoud T. et al. (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28: 5110–5115.
2. Bachelot T. Bourgier C. Cropet C. Ray-Coquard I. Ferrero J. Freyer G. et al. (2012) Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30: 2718–2724.
3. Baselga J. Campone M. Piccart M. Burris H. 3rd Rugo H. Sahmoud T. et al. (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366: 520–529.
4. Baselga J. Semiglazov V. van Dam P. Manikhas A. Bellet M. Mayordomo J. et al. (2009) 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.
5. Bendell J. Rodon J. Burris H. de Jonge M. Verweij J. Birle D. et al. (2012) 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.
6. Bertucci M. Mitchell C. (2013) Phosphoinositide 3-kinase and INPP4B in human breast cancer. Ann N Y Acad Sci 1280: 1–5.
7. Bowles D. Ma W. Senzer N. Brahmer J. Adjei A. Davies M. et al. (2013) A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer 109: 1085–1092.
8. Breuleux M. Klopfenstein M. Stephan C. Doughty C. Barys L. Maira S. et al. (2009) Increased AKT S 473 phosphorylation after mTORC 1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR Inhibition. Mol Cancer Ther 8: 742–753.
9. Bruhn M. Pearson R. Hannan R. Sheppard K. (2013) AKT-independent PI3-K signaling in cancer – emerging role for SGK3. Cancer Manag Res 5: 281–292.
10. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490: 61–70.
11. Cantley L. (2002) The phosphoinositide 3-kinase pathway. Science 296: 1655–1657.
12. Di Nicolantonio F. Arena S. Tabernero J. Grosso S. Molinari F. Macarulla T. et al. (2010) Deregulation of the PI3K and Kras signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 120: 2858–2866.
13. Dowling R. Topisirovic I. Fonseca B. Sonenberg N. (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 1804: 433–439.
14. Dowsett M. Ebbs S. Dixon J. Skene A. Griffith C. Boeddinghaus I. et al. (2005) Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer – a study from the impact trialists. J Clin Oncol 23: 2477–2492.
15. Dowsett M. Smith I. Ebbs S. Dixon J. Skene A. A'Hern R. et al. (2007) Prognostic value of KI 67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 99: 167–170.
16. Elkabets M. Vora S. Juric D. Morse N. Mino-Kenudson M. Muranen T. et al. (2013) Mtorc 1 Inhibition Is Required for Sensitivity to Pi3k P110alpha Inhibitors in Pik3ca-Mutant Breast Cancer. Sci Transl Med 5: 196ra99.
17. Ellard S. Clemons M. Gelmon K. Norris B. Kennecke H. Chia S. et al. (2009) Randomized phase II study comparing two schedules of everolimus in patients with recurrent / metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 27: 4536–4541.
18. Engelman J. Luo J. Cantley L. (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7: 606–619.
19. Hoeflich K. O'Brien C. Boyd Z. Cavet G. Guerrero S. Jung K. et al. (2009) In vivo antitumor activity of mek and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 15: 4649–4664.
20. Holz M. (2012) The role of S6K1 in ER-positive breast cancer. Cell Cycle 11: 3159–3165.
21. Hong D. Bowles D. Falchook G. Messersmith W. George G. O'Bryant C. et al. (2012) 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.
22. Hortobagyi G. Piccart-Gebhart M. Rugo H. Burris H. Campone M. Noguchi S. et al. (2013) Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol 31(Suppl.): abstract LBA509.
23. Hu L. Hofmann J. Lu Y. Mills G. Jaffe R. (2002) Inhibition of phosphatidylinositol 3’-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 62: 1087–1092.
24. Hurvitz S. Dalenc F. Campone M. O'Regan R. Tjan-Heijnen V. Gligorov J. et al. (2013) A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res Treat 141: 437–446.
25. Ihle N. Lemos R. Jr Wipf P. Yacoub A. Mitchell C. Siwak D. et al. (2009) 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.
26. Ihle N. Williams R. Chow S. Chew W. Berggren M. Paine-Murrieta G. et al. (2004) Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 3: 763–772.
27. Janku F. Tsimberidou A. Garrido-Laguna I. Wang X. Luthra R. Hong D. et al. (2011) PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther 10: 558–565.
28. Janku F. Wheler J. Naing A. Falchook G. Hong D. Stepanek V. et al. (2013) PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res 73: 276–284.
29. Janku F. Wheler J. Westin S. Moulder S. Naing A. Tsimberidou A. et al. (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 30: 777–782.
30. Jerusalem G. Fasolo A. Dieras V. Cardoso F. Bergh J. Vittori L. et al. (2011) Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 125: 447–455.
31. Juric D. Baselga J. (2012) Tumor genetic testing for patient selection in phase I clinical trials: the case of PI3K inhibitors. J Clin Oncol 30: 765–766.
32. Kenerson H. Aicher L. True L. Yeung R. (2002) Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 62: 5645–5650.
33. Kittaneh M. Montero A. Gluck S. (2013) Molecular profiling for breast cancer: a comprehensive review. Biomark Cancer 5: 61–70.
34. Lehmann B. Bauer J. Chen X. Sanders M. Chakravarthy A. Shyr Y. et al. (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121: 2750–2767.
35. Liu N. Rowley B. Bull C. Schneider C. Haegebarth A. Schatz C. et al. (2013) Bay 80–6946 is a highly selective intravenous PI3K inhibitor with potent P110alpha and P110delta activities in tumor cell lines and xenograft models. Mol Cancer Ther 12: 2319–2330.
36. Maehama T. Dixon J. (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375–13378.
37. Maira S. Pecchi S. Huang A. Burger M. Knapp M. Sterker D. et al. (2012) Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 11: 317–328.
38. Markman B. Tabernero J. Krop I. Shapiro G. Siu L. Chen L. et al. (2012) Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT 226 in patients with advanced solid tumors. Ann Oncol 23: 2399–2408.
39. McDonald G. Sullivan R. Pare G. Graham C. (2010) Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression. Exp Cell Res 316: 3197–3206.
40. Meric-Bernstam F. Akcakanat A. Chen H. Do K. Sangai T. Adkins F. et al. (2012) PIK3CA/PTEN mutations and AKT activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res 18: 1777–1789.
41. Muellner M. Uras I. Gapp B. Kerzendorfer C. Smida M. Lechtermann H. et al. (2011) A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nat Chem Biol 7: 787–793.
42. Nahta R. (2012) Pharmacological strategies to overcome HER 2 cross-talk and trastuzumab resistance. Curr Med Chem 19: 1065–1075.
43. Ng S. Tsao M. Chow S. Hedley D. (2000) Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res 60: 5451–5455.
44. Nguyen D. Chen G. Reddy R. Tsai W. Schrump W. Cole G. Jr et al. (2004) Potentiation of paclitaxel cytotoxicity in lung and esophageal cancer cells by pharmacologic inhibition of the phosphoinositide 3-kinase/protein kinase B (Akt)-mediated signaling pathway. J Thorac Cardiovasc Surg 127: 365–375.
45. Noh W. Kim Y. Kim M. Koh J. Kim H. Moon N. et al. (2008) Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables. Breast Cancer Res Treat 110: 477–483.
46. Noh W. Mondesire W. Peng J. Jian W. Zhang H. Dong J. et al. (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10: 1013–1023.
47. O'Brien C. Wallin J. Sampath D. Guhathakurta D. Savage H. Punnoose E. et al. (2010) Predictive biomarkers of sensitivity to the phosphatidylinositol 3’ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res 16: 3670–3683.
48. Oda K. Stokoe D. Taketani Y. McCormick F. (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65: 10669–10673.
49. Oliveira M., Navarro, A. de Mattos-Arruda L. Sánchez-Ollé G. Bellet M. Balmaña J. et al. (2012) PI3K pathway (PI3KP) dysregulation and response to PAN-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3KPI) in metastatic breast cancer (MBC) patients (Pts). J Clin Oncol 30(Suppl.): abstract 509.
50. O'Regan R. Ozguroglu M. Andre F. Toi M. Jerusalem G. Wilks S. et al. (2013) Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab- resistant, advanced breast cancer (BOLERO-3). J Clin Oncol 31(Suppl.): abstract 505.
51. O'Reilly T. McSheehy P. (2010) Biomarker development for the clinical activity of the mTOR inhibitor everolimus (Rad001): processes, limitations, and further proposals. Transl Oncol 3: 65–79.
52. Paplomata E. O'Regan R. (2013) New and emerging treatments for estrogen receptor-positive Breast cancer: focus on everolimus. Ther Clin Risk Manag 9: 27–36.
53. Paplomata E. Zelnak A. O'Regan R. (2013) Everolimus: side effect profile and management of toxicities in breast cancer. Breast Cancer Res Treat 140: 453–462.
54. Peddi P. Hurvitz S. (2014) PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer. J Neurooncol 117 (1): 7–13.
55. Perou C. Sorlie T. Eisen M. van de Rijn M. Jeffrey S. Rees C. et al. (2000) Molecular portraits of human breast tumours. Nature 406: 747–752.
56. Piccart-Gebhart M., Noguchi, S. Pritchard K. Burris H. Rugo H. Gnant M. (2012) Everolimus for postmenopausal women with advanced breast cancer: updated results of the BOLERO-2 phase IIII trial. J Clin Oncol 30(Suppl.): abstract 559.
57. Powis G. Hill S. Frew T. Sherrill K. (1995) Inhibitors of phospholipid intracellular signaling as antiproliferative agents. Med Res Rev 15: 121–138.
58. Rivera V. Squillace R. Miller D. Berk L. Wardwell S. Ning Y. et al. (2011) Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 10: 1059–1071.
59. Samuels Y. Velculescu V. (2004) Oncogenic mutations of PIK3Ca in human cancers. Cell Cycle 3: 1221–1224.
60. Sangai T. Akcakanat A. Chen H. Tarco E. Wu Y. Do K. et al. (2012) Biomarkers of response to AKT inhibitor MK-2206 in breast cancer. Clin Cancer Res 18: 5816–5828.
61. Sarbassov D. Ali S. Sengupta S. Sheen J. Hsu P. Bagley A. et al. (2006) Prolonged rapamycin treatment inhibits mtORC 2 assembly and AKT/PKB. Mol Cell 22: 159–168.
62. Saura C. Bendell J. Jerusalem G. Su S. Ru Q. de Buck S. et al. (2014) Phase Ib study of buparlisib plus trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on trastuzumab-based therapy. Clin Cancer Res 20 (7): 1–11.
63. Serra V. Eichhorn P. Garcia-Garcia C. Ibrahim Y. Prudkin L. Sanchez G. et al. (2013) RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest 123: 2551–2563.
64. Siegel R. Naishadham D. Jemal A. (2013) Cancer Statistics, 2013. CA Cancer J Clin 63: 11–30.
65. Sorlie T. Perou C. Tibshirani R. Aas T. Geisler S. Johnsen H. et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98: 10869–10874.
66. Sorlie T. Tibshirani R. Parker J. Hastie T. Marron J. Nobel A. et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100: 8418–8423.
67. Stemke-Hale K. Gonzalez-Angulo A. Lluch A. Neve R. Kuo W. Davies M. et al. (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68: 6084–6091.
68. Treilleux I. Arnedos M. Cropet C. Ferrero J. Lacourtoisie S. Spaeth D. et al. (2013) Predictive markers of everolimus efficacy in hormone receptor positive (HR+) metastatic breast cancer (MBC): final results of the TAMRAD Trial Translational Study. J Clin Oncol 31(Suppl.): abstract 510.
69. Vasudevan K. Barbie D. Davies M. Rabinovsky R. McNear C. Kim J. et al. (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16: 21–32.
70. Wander S. Hennessy B. Slingerland J. (2011) Next-generation mtOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 121: 1231–1241.
71. Wee S. Wiederschain D. Maira S. Loo A. Miller C. Debeaumont R. et al. (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A 105: 13057–13062.
72. Weigelt B. Warne P. Downward J. (2011) PIK3Ca mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 30: 3222–3233.
73. Wolff A. Lazar A. Bondarenko I. Garin A. Brincat S. Chow L. et al. (2013) Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 31: 195–202.
74. Zhang W. Haines B. Efferson C. Zhu J. Ware C. Kunii K. et al. (2012) Evidence of mTOR activation by an AKT-independent mechanism provides support for the combined treatment of PTEN-deficient prostate tumors with mTOR and AKT inhibitors. Transl Oncol 5: 422–429.
75. Zhao L. Vogt P. (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27: 5486–5496.