Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: Old targets new hope

Cancer Treatment Reviews

Volumn 39, Issue 5, 2013, Pages 403-412

  De, Pradip ^a   Miskimins, Keith ^a   Dey, Nandini ^a   Leyland Jones, Brian ^a  

^a SANFORD RESEARCH   (United States)

Author keywords

Breast cancer; ER+; HER2; MTOR kinase inhibitor; PI3K; Triple negative basal type

Indexed keywords

ANTINEOPLASTIC AGENT; APITOLISIB; AZD 2014; AZD 8055; CC223; DALOTOZUMAB; DOCETAXEL; EPIRUBICIN; EVEROLIMUS; GSK2126458; INK128; LETROZOLE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MONOCLONAL ANTIBODY; NVPBEZ235; NVPBGT22; OSIO27; PACLITAXEL; PALOMID 529; PERTUZUMAB; PF04691502; RIDAFOROLIMUS; SORAFENIB; SUNITINIB; TAMOXIFEN; TEMSIROLIMUS; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; XL388;

ADJUVANT CHEMOTHERAPY; APOPTOSIS; BINDING SITE; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER GRADING; CANCER GROWTH; CANCER INHIBITION; CANCER RECURRENCE; CELL PROLIFERATION; CELL SURVIVAL; DNA DAMAGE; DNA METHYLATION; DOWN REGULATION; DRUG APPROVAL; DRUG DEVELOPMENT; DRUG SAFETY; DRUG SCREENING; ENZYME ACTIVITY; ENZYME INHIBITION; GAIN OF FUNCTION MUTATION; GENE MUTATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGNOSIS; PROTEIN DEPLETION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; TREATMENT DURATION; TRIPLE NEGATIVE BREAST CANCER; TUMOR MICROENVIRONMENT; UPREGULATION;

ANTIBIOTICS, ANTINEOPLASTIC; BREAST NEOPLASMS; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84876989771     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2012.12.002     Document Type: Review

References (94)

1. Hay N., Sonenberg N. Upstream and downstream of mTOR. Genes & Development 2004, 18:1926-1945.
2. Oldham S., Hafen E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends in Cell Biology 2003, 13:79-85.
3. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell 2006, 124:471-484.
4. Towler M.C., Hardie D.G. AMP-activated protein kinase in metabolic control and insulin signaling. Circulation Research 2007, 100:328-341.
5. Porstmann T., Santos C.R., Griffiths B., Cully M., Wu M., Leevers S., et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metabolism 2008, 8:224-236.
6. Chan E.Y. mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex. Science Signaling 2009, 2:pe51.
7. Saal L.H., Gruvberger-Saal S.K., Persson C., Lovgren K., Jumppanen M., Staaf J., et al. Recurrent gross mutations of the PTEN tumor suppressor gene in BCs with deficient DSB repair. Nature Genetics 2008, 40:102-107.
8. Barlund M., Monni O., Kononen J., Cornelison R., Torhorst J., Sauter G., et al. Multiple genes at 17q23 undergo amplification and overexpression in BC. Cancer Research 2000, 60:5340-5344.
9. Samuels Y., Ericson K. Oncogenic PI3K and its role in cancer. Current Opinion in Oncology 2006, 18:77-82.
10. Dowling R.J., Topisirovic I., Fonseca B.D., Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochimica et Biophysica Acta 2010, 1804:433-439.
11. Guertin D.A., Sabatini D.M. Defining the role of mTOR in cancer. Cancer Cell 2007, 12:9-22.
12. Sarbassov D.D., Ali S.M., Kim D.H., Guertin D.A., Latek R.R., Erdjument-Bromage H., et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology: CB 2004, 14:1296-1302.
13. Sun S.Y., Rosenberg L.M., Wang X., Zhou Z., Yue P., Fu H., et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Research 2005, 65:7052-7058.
14. O'Reilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., et al. MTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Research 2006, 66:1500-1508.
15. Di Cosimo S., Bendell J.C., Cervantes-Ruiperez A., Roda D., Prudkin L., Stein M.N., et al. A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors. ASCO Annual Meeting: Journal of Clinical Oncology 2010, Abstract # 3008.
16. Wu M.J., Chang C.H., Chiu Y.T., Wen M.C., Shu K.H., Li J.R., et al. Rictor-dependent AKT activation and inhibition of urothelial carcinoma by rapamycin. Urologic Oncology 2012, 30:69-77.
17. Rojo F., Najera L., Lirola J., Jimenez J., Guzman M., Sabadell M.D., et al. 4E-binding protein 1, a cell signaling hallmark in BC that correlates with pathologic grade and prognosis. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2007, 13:81-89.
18. Hsu P.P., Kang S.A., Rameseder J., Zhang Y., Ottina K.A., Lim D., et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011, 332:1317-1322.
19. Yu Y., Yoon S.O., Poulogiannis G., Yang Q., Ma X.M., Villen J., et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 2011, 332:1322-1326.
20. Holt L.J., Siddle K. Grb10 and Grb14: enigmatic regulators of insulin action - and more?. The Biochemical Journal 2005, 388:393-406.
21. Lang S.A., Hackl C., Moser C., Fichtner-Feigl S., Koehl G.E., Schlitt H.J., et al. Implication of RICTOR in the mTOR inhibitor-mediated induction of insulin-like growth factor-I receptor (IGF-IR) and human epidermal growth factor receptor-2 (Her2) expression in gastrointestinal cancer cells. Biochimica et Biophysica Acta 2010, 1803:435-442.
22. Carracedo A., Ma L., Teruya-Feldstein J., Rojo F., Salmena L., Alimonti A., et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. The Journal of Clinical Investigation 2008, 118:3065-3074.
23. De P, Sun Y, Dey N, Leyland-Jones B. Preclinical efficacy of the novel dual PI3K/mTOR inhibitor, BEZ235 compared with RAD001 in HER2+ breast tumor cells. In: 102th AACR Meeting. Orlando, FL, 2011 [Abstract # 4496].
24. Feldman M.E., Apsel B., Uotila A., Loewith R., Knight Z.A., Ruggero D., et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biology 2009, 7:e38.
25. Thoreen C.C., Kang S.A., Chang J.W., Liu Q., Zhang J., Gao Y., et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. The Journal of Biological Chemistry 2009, 284:8023-8032.
26. Yu K., Toral-Barza L., Shi C., Zhang W.G., Lucas J., Shor B., et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Research 2009, 69:6232-6240.
27. Xue Q., Hopkins B., Perruzzi C., Udayakumar D., Sherris D., Benjamin L.E. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Research 2008, 68:9551-9557.
28. Janes M.R., Limon J.J., So L., Chen J., Lim R.J., Chavez M.A., et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nature Medicine 2010, 16:205-213.
29. Falcon B.L., Barr S., Gokhale P.C., Chou J., Fogarty J., Depeille P., et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Research 2011, 71:1573-1583.
30. Gulhati P., Cai Q., Li J., Liu J., Rychahou P.G., Qiu S., et al. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2009, 15:7207-7216.
31. Toschi A., Lee E., Gadir N., Ohh M., Foster D.A. Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. The Journal of Biological Chemistry 2008, 283:34495-34499.
32. Gupta M., Hendrickson A.E., Yun S.S., Han J.J., Schneider P.A., Koh B.D., et al. Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. Blood 2012, 119:476-487.
33. De P, Sun Y, Hui W, Rommel C, Liu Y, Dey N, et al. Efficacy of INK128, an mTORC1/mTORC2 kinase inhibitor, in BC models driven by HER2-PI3K-AKT-mTOR pathway. ASCO, Chicago, IL, 2012 [Abstract # 626].
34. Chan S., Scheulen M.E., Johnston S.R.D., et al. A phase II study of two dose levels of CCI-779 in locally advanced or metasatic BC failing prior anthracyclines and/or taxanes regimens. Proceedings of the American Society for Clinical Oncology 2003, 22:A774.
35. Miller T.W., Hennessy B.T., Gonzalez-Angulo A.M., Fox E.M., Mills G.B., Chen H., et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human BC. The Journal of Clinical Investigation 2010, 120:2406-2413.
36. Miller T.W., Perez-Torres M., Narasanna A., Guix M., Stal O., Perez-Tenorio G., et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in BC. Cancer Research 2009, 69:4192-4201.
37. Shou J., Massarweh S., Osborne C.K., Wakeling A.E., Ali S., Weiss H., et al. Mechanisms of tamoxifen resistance. Increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive BC. Journal of the National Cancer Institute 2004, 96:926-935.
38. Rhodes L.V., Short S.P., Neel N.F., Salvo V.A., Zhu Y., Elliott S., et al. Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human BC. Cancer Research 2011, 71:603-613.
39. Zheng H., Dai T., Zhou B., Zhu J., Huang H., Wang M., et al. SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. Atherosclerosis 2008, 201:36-42.
40. Liang Z., Brooks J., Willard M., Liang K., Yoon Y., Kang S., et al. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochemical and Biophysical Research Communications 2007, 359:716-722.
41. Casa A.J., Dearth R.K., Litzenburger B.C., Lee A.V., Cui X. The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Frontiers in Bioscience: A Journal and Virtual Library 2008, 13:3273-3287.
42. Maor S., Mayer D., Yarden R.I., Lee A.V., Sarfstein R., Werner H., et al. Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. The Journal of Endocrinology 2006, 191:605-612.
43. Tanno S., Tanno S., Mitsuuchi Y., Altomare D.A., Xiao G.H., Testa J.R. AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Research 2001, 61:589-593.
44. Dupont J., LeRoith D. Insulin and insulin-like growth factor I receptors: similarities and differences in signal transduction. Hormone Research 2001, 55(Suppl. 2):22-26.
45. Lane H.A., Lebwohl D. Future directions in the treatment of hormone-sensitive advanced BC: the RAD001 (Everolimus)-letrozole clinical program. Seminars in Oncology 2006, 33:S18-S25.
46. deGraffenried L.A., Friedrichs W.E., Russell D.H., Donzis E.J., Middleton A.K., Silva J.M. Inhibition of mTOR activity restores tamoxifen response in BC cells with aberrant Akt Activity. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2004, 10:8059-8067.
47. Johnston S.R. Enhancing the efficacy of hormonal agents with selected targeted agents. Clinical BC 2009, 9(Suppl. 1):S28-S36.
48. Janku F., Tsimberidou A.M., Garrido-Laguna I., Wang X., Luthra R., Hong D.S., et al. PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Molecular Cancer Therapeutics 2011, 10:558-565.
49. Stemke-Hale K., Gonzalez-Angulo A.M., Lluch A., Neve R.M., Kuo W.L., Davies M., et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in BC. Cancer Research 2008, 68:6084-6091.
50. Dupont Jensen J., Laenkholm A.V., Knoop A., Ewertz M., Bandaru R., Liu W. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in BC. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2011, 17:667-677.
51. Hennessy B.T., Smith D.L., Ram P.T., Lu Y., Mills G.B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Reviews Drug Discovery 2005, 4:988-1004.
52. Crowder R.J., Phommaly C., Tao Y., Hoog J., Luo J., Perou C.M., et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive BC. Cancer Research 2009, 69:3955-3962.
53. Kirkegaard T., Witton C.J., McGlynn L.M., Tovey S.M., Dunne B., Lyon A., et al. AKT activation predicts outcome in BC patients treated with tamoxifen. The Journal of Pathology 2005, 207:139-146.
54. Tokunaga E., Kataoka A., Kimura Y., Oki E., Mashino K., Nishida K., et al. The association between Akt activation and resistance to hormone therapy in metastatic BC. European Journal of Cancer 2006, 42:629-635.
55. Rudloff J., Boulay A., Zumstein-Mecker S., Evans D.B., O'Reilly T., Lane H. The mTOR pathway in estrogen response: a potential for combining the rapamycin derivative RAD001 with the aromatase inhibitor letrozole in breast carcinomas. Proceedings of American Association for Cancer Research 2004, Abstract # A5619.
56. Boulay A., Rudloff J., Ye J., Zumstein-Mecker S., O'Reilly T., Evans D.B., et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of BC. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2005, 11:5319-5328.
57. Baselga J., Semiglazov V., van Dam P., Manikhas A., Bellet M., Mayordomo J., et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive BC. Journal of Clinical Oncology: An Official Journal of the American Society of Clinical Oncology 2009, 27:2630-2637.
58. Bachelot Tea A. GINECO Randomized Phase II Trial of Everolimus in Combination with Tamoxifen Versus Tamoxifen Alone in Patients (pts) with Hormone-Receptor Positive, HER2 Negative Metastatic BC (MBC) with Prior Exposure to Aromatase Inhibitors (AI). In: 33rd Annual San Antonio BC Symposium, San Antonio 2010 [Abstract #S1-6].
59. Bachelot T., Bourgier C., Cropet C., Ray-Coquard I., Ferrero J.M., Freyer G., et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic BC with prior exposure to aromatase inhibitors: a GINECO Study. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2012, 30:2718-2724.
60. Baselga J., Campone M., Piccart M., Burris H.A., Rugo H.S., Sahmoud T., et al. Everolimus in postmenopausal hormone-receptor-positive advanced BC. The New England Journal of Medicine 2012, 366:520-529.
61. Guichard SM, Howard Z, Heathcote D, Roth M, Hughes G, et al. AZD2014, a dual mTORC1 and mTORC2 inhibitor is differentiated from allosteric inhibitors of mTORC1 in ER+ BC. 103rd Annual Meeting of the American Association for Cancer Research. Chicago, IL: American Association for Cancer Research; 2012 [Abstract # 917].
62. Citri A., Yarden Y. EGF-ERBB signalling: towards the systems level. Nature Reviews Molecular Cell Biology 2006, 7:505-516.
63. Gianni L., Pienkowski T., Im Y.H., Roman L., Tseng L.M., Liu M.C., et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive BC (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The Lancet Oncology 2012, 13:25-32.
64. Baselga J., Cortes J., Kim S.B., Im S.A., Hegg R., Im Y.H., et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic BC. The New England Journal of Medicine 2012, 366:109-119.
65. Junttila T.T., Akita R.W., Parsons K., Fields C. Lewis Phillips GD, Friedman LS, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 2009, 15:429-440.
66. Mohsin S.K., Weiss H.L., Gutierrez M.C., Chamness G.C., Schiff R., Digiovanna M.P., et al. Neoadjuvant trastuzumab induces apoptosis in primary BCs. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2005, 23:2460-2468.
67. Perez-Tenorio G., Alkhori L., Olsson B., Waltersson M.A., Nordenskjold B., Rutqvist L.E., et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in BC. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2007, 13:3577-3584.
68. Berns K., Horlings H.M., Hennessy B.T., Madiredjo M., Hijmans E.M., Beelen K., et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in BC. Cancer Cell 2007, 12:395-402.
69. Fujita T., Doihara H., Kawasaki K., Takabatake D., Takahashi H., Washio K., et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing BC. British Journal of Cancer 2006, 94:247-252.
70. Huober J, Loibl S, Untch M, et al. New Molecular biomarkers for resistance to trastuzumab in primary HER2 positive BC - a translational Investigation from the Neoadjuvant GeparQuattro Study. In: 33rd Annual San Antonio BC Symposium, San Antonio, TX, 2010 [Abstract # PD02-6].
71. Lee-Hoeflich S.T., Crocker L., Yao E., Pham T., Munroe X., Hoeflich K.P., et al. A central role for HER3 in HER2-amplified BC: implications for targeted therapy. Cancer Research 2008, 68:5878-5887.
72. Chakrabarty A., Sanchez V., Kuba M.G., Rinehart C., Arteaga C.L. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proceedings of the National Academy of Sciences of the United States of America 2012, 109:2718-2723.
73. André F., Campone M., Hurvitz S.A., Vittori L., Pylvaenaeinen I., Sahmoud T., et al. Multicenter phase I clinical trial of daily and weekly RAD001 in combination with weekly paclitaxel and trastuzumab in patients with HER2-overexpressing metastatic BC with prior resistance to trastuzumab. Journal of Clinical Oncology 2008, Abstract # 1003.
74. Jerusalem G.H., Vieras V., Cardoso F., et al. Multicenter phase I clinical trial of daily and weekly RAD001 in combination with vinorelbine and trastuzumab in patients with HER2-overexpressing metastatic BC with prior resistance to trastuzumab. Journal of Clinical Oncology 2008, Abstract # 1057.
75. Andre F., Campone M., O'Regan R., Manlius C., Massacesi C., Sahmoud T., et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic BC pretreated with trastuzumab. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2010, 28:5110-5115.
76. Morrow P.K., Wulf G.M., Ensor J., Booser D.J., Moore J.A., Flores P.R., et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic BC who progressed on trastuzumab-based therapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2011, 29:3126-3132.
77. Gajria D, King T, Pannu H, Sakr R, Seidman A, S M, et al. Combined inhibition of mTORC1 with temisirolimus and HER2 with neratinib: a phase I/II study in patients with metastatic HER2 amplified or triple negative BC. In: San Antonio BC Symposium San Antonio, TX: AACR; 2011.
78. Saal L.H., Holm K., Maurer M., Memeo L., Su T., Wang X., et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Research 2005, 65:2554-2559.
79. Saal L.H., Johansson P., Holm K., Gruvberger-Saal S.K., She Q.B., Maurer M., et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proceedings of the National Academy of Sciences of the United States of America 2007, 104:7564-7569.
80. Marty B., Maire V., Gravier E., Rigaill G., Vincent-Salomon A., Kappler M., et al. Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like BC cells. BC Research: BCR 2008, 10:R101.
81. Lopez-Knowles E., O'Toole S.A., McNeil C.M., Millar E.K., Qiu M.R., Crea P., et al. PI3K pathway activation in BC is associated with the basal-like phenotype and cancer-specific mortality. International Journal of Cancer 2010, 126:1121-1131.
82. Martins F.C., De S., Almendro V., Gonen M., Park S.Y., Blum J.L., et al. Evolutionary pathways in BRCA1-associated breast tumors. Cancer Discovery 2012, 2:503-511.
83. Umemura S., Yoshida S., Ohta Y., Naito K., Osamura R.Y., Tokuda Y. Increased phosphorylation of Akt in triple-negative BCs. Cancer Science 2007, 98:1889-1892.
84. Chacon R.D., Triple-negative Costanzo.M.V. BC Research: BCR 2010, 12(Suppl. 2):S3.
85. Farmer H., McCabe N., Lord C.J., Tutt A.N., Johnson D.A., Richardson T.B., et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434:917-921.
86. Bhattacharyya A., Ear U.S., Koller B.H., Weichselbaum R.R., Bishop D.K. The BC susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. The Journal of Biological Chemistry 2000, 275:23899-23903.
87. Turner N., Tutt A., Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nature Reviews Cancer 2004, 4:814-819.
88. Kumar A., Fernandez-Capetillo O., Carrera A.C. Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair. Proceedings of the National Academy of Sciences of the United States of America 2010, 107:7491-7496.
89. Ibrahim Y.H., Garcia-Garcia C., Serra V., He L., Torres-Lockhart K., Prat A., et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA proficient triple negative BC to PARP inhibition. Cancer Discovery 2012.
90. Juvekar A., Burga L.N., Hu H., Lunsford E.P., Ibrahim Y.H., Balmana J., et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for a mouse model of BRCA1-related BC. Cancer Discovery 2012.
91. The Cancer Genome Atlas N, Genome sequencing centres: Washington University in St L, Koboldt D.C., Fulton R.S., McLellan M.D., Schmidt H., et al. Comprehensive molecular portraits of human breast tumours. Nature 2012.
92. Marshall G., Howard Z., Dry J., Fenton S., Heathcote D., Gray N., et al. Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochemical Society Transactions 2011, 39:456-459.
93. Benjamin D., Colombi M., Moroni C., Hall M.N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Reviews Drug Discovery 2011, 10:868-880.
94. Albert S., Serova M., Dreyer C., Sablin M.P., Faivre S., Raymond E. New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Expert Opinion on Investigational Drugs 2010, 19:919-930.