Short Communication: Updates on AKT Inhibition in Estrogen Receptor Positive Breast Cancer
Main Article Content
Abstract
Activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling is associated with endocrine resistance in estrogen receptor positive (ER+) breast cancer. AKT is an important downstream effector of the PI3K signaling pathway, regulating key cellular functions related to cancer progression and survival. Preclinical evidence supports the evaluation of AKT inhibitors as a treatment strategy for patients with ER+ breast cancer. Early phase clinical trials of AKT inhibitors provides preliminary efficacy and key toxicity profiles. Clinical trials have been focused on combining AKT inhibitors with hormonal therapy or cytotoxic chemotherapy. Here we present an update on the clinical investigation of these agents.
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How to Cite
PARK, Haeseong; MA, Cynthia.
Short Communication: Updates on AKT Inhibition in Estrogen Receptor Positive Breast Cancer.
Medical Research Archives, [S.l.], v. 6, n. 1, jan. 2018.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1614>. Date accessed: 15 nov. 2024.
doi: https://doi.org/10.18103/mra.v6i1.1614.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261-75.
2. Cantley LC. The Phosphoinositide 3-Kinase Pathway. Science. 2002;296 (5573):1655-7.
3. Ma CX, Crowder RJ, Ellis MJ. Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors. Steroids. 2011;76(8):750-2.
4. Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev. 2014;40(7):862-71.
5. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9.
6. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer research. 2006;66(3):1500-8.
7. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26(13):1932-40.
8. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, et al. Stand up to cancer phase ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(12):1202-9.
9. Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, et al. A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor Positive Metastatic Breast Cancer. Clinical Cancer Research. 2016.
10. Ma CX, Luo J, Naughton M, Ademuyiwa FO, Suresh R, Griffith M, et al. A phase 1 trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer. Clin Cancer Res. 2015.
11. Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, et al., editors. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. San Antonio Breast Cancer Symposium; 2015; San Antonio, Texas.
12. Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997;88(4):435-7.
13. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes & development. 1999;13(22):2905-27.
14. Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America. 1987;84(14):5034-7.
15. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96(6):857-68.
16. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-74.
17. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19(1):58-71.
18. Virtakoivu R, Pellinen T, Rantala JK, Perala M, Ivaska J. Distinct roles of AKT isoforms in regulating beta1-integrin activity, migration, and invasion in prostate cancer. Mol Biol Cell. 2012;23(17):3357-69.
19. Dillon RL, Muller WJ. Distinct biological roles for the akt family in mammary tumor progression. Cancer Res. 2010;70(11):4260-4.
20. Li CW, Xia W, Lim SO, Hsu JL, Huo L, Wu Y, et al. AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation. Cancer Res. 2016;76(6):1451-62.
21. Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal. 2006;18(12):2262-71.
22. Riggio M, Perrone MC, Polo ML, Rodriguez MJ, May M, Abba M, et al. AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins. Sci Rep. 2017;7:44244.
23. Grabinski N, Mollmann K, Milde-Langosch K, Muller V, Schumacher U, Brandt B, et al. AKT3 regulates ErbB2, ErbB3 and estrogen receptor alpha expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. Cell Signal. 2014;26(5):1021-9.
24. Stottrup C, Tsang T, Chin YR. Upregulation of AKT3 Confers Resistance to the AKT Inhibitor MK2206 in Breast Cancer. Molecular cancer therapeutics. 2016;15(8):1964-74.
25. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353-60.
26. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.
27. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012;18(20):5816-28.
28. Beaver JA, Gustin JP, Yi KH, Rajpurohit A, Thomas M, Gilbert SF, et al. PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19(19):5413-22.
29. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001;276(13):9817-24.
30. Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, et al. Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res. 2001;61(16):5985-91.
31. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406-13.
32. Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res. 2006;66(7):3903-11.
33. Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 2010;12(3):R40.
34. Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol. 2005;207(2):139-46.
35. Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, et al. A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(11):2650-8.
36. Ribas R, Pancholi S, Guest SK, Marangoni E, Gao Q, Thuleau A, et al. AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo. Molecular cancer therapeutics. 2015;14(9):2035-48.
37. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Molecular cancer therapeutics. 2010;9(7):1956-67.
38. Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Molecular cancer therapeutics. 2012;11(4):873-87.
39. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(35):4688-95.
40. Yap TA, Yan L, Patnaik A, Tunariu N, Biondo A, Fearen I, et al. Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(22):5672-85.
41. Doi T, Tamura K, Tanabe Y, Yonemori K, Yoshino T, Fuse N, et al. Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;76(2):409-16.
42. Gonzalez-Angulo AM, Krop I, Akcakanat A, Chen H, Liu S, Li Y, et al. SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J Natl Cancer Inst. 2015;107(3).
43. Tripathy D, Chien AJ, Hylton N, Buxton MB, Ewing CA, Wallace AM, 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, (suppl; abstr 524). 2015.
44. Chien AJ, Cockerill A, Fancourt C, Schmidt E, Moasser MM, Rugo HS, et al. A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies. Breast cancer research and treatment. 2016;155(3):521-30.
45. Ma CX, Suman V, Goetz MP, Northfelt DW, Burkard ME, Ademuyiwa F, et al. A Phase II trial of neoadjuvant MK2206, an AKT inhibitor, with anastrozole in clinical stage 2 or 3 PIK3CA mutant ER positive and HER2 negative breast cancer. Clinical Cancer Research. 2017.
46. Hyman DM, Smyth L, Bedard PL, Oza A, Dean E, Armstrong A, et al. AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors. [Abstract]. In: Proceedings of the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, Massachusetts Philadelphia (PA): AACR. 2015.
47. Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, et al. AKT Inhibition in Solid Tumors With AKT1 Mutations. Journal of Clinical Oncology. 2017;35(20):2251-9.
48. Andre F, Bachelot T, Commo F, Campone M, Arnedos M, Dieras V, et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 2014;15(3):267-74.
49. Fu X, Creighton CJ, Biswal NC, Kumar V, Shea M, Herrera S, et al. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Res. 2014;16(5):430.
50. Ren H, Guo H, Thakur A, Zhang S, Wang T, Liang Y, et al. Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells. Oncotarget. 2016.
51. Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(4):739-48.
52. Luey BC, May FE. Insulin-like growth factors are essential to prevent anoikis in oestrogen-responsive breast cancer cells: importance of the type I IGF receptor and PI3-kinase/Akt pathway. Mol Cancer. 2016;15:8.
53. Mata R, Palladino C, Nicolosi ML, Lo Presti AR, Malaguarnera R, Ragusa M, et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget. 2016;7(7):7683-700.
54. Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 2013;15(4):R55.
55. Brana I, Berger R, Golan T, Haluska P, Edenfield J, Fiorica J, et al. A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. Br J Cancer. 2014;111(10):1932-44.
56. Akt Inhibitor MK2206 in Treating Patients With Advanced Breast Cancer, https://clinicaltrials.gov/ct2/show/results/NCT01277757 [Accessed March 22, 2017] [
57. Wisinski KB, Tevaarwerk AJ, Burkard ME, Rampurwala M, Eickhoff J, Bell MC, et al. Phase I Study of an AKT Inhibitor (MK-2206) Combined with Lapatinib in Adult Solid Tumors Followed by Dose Expansion in Advanced HER2+ Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(11):2659-67.
58. Gupta S, Argiles G, Munster PN, Hollebecque A, Dajani O, Cheng JD, et al. A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(23):5235-44.
59. Hudis C, Swanton C, Janjigian YY, Lee R, Sutherland S, Lehman R, et al. A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors. Breast Cancer Res. 2013;15(6):R110.
60. Tamura K, Hashimoto J, Tanabe Y, Kodaira M, Yonemori K, Seto T, et al. Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016;77(4):787-95.
61. DM Hyman, L Smyth, PL Bedard, A Oza, E Dean, A Armstrong, et al. AZD5363, a catalytic pan-AKT inhibitor, in AKT1 E17K mutation positive advanced solid tumors. Presented at at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2015 [Abstract].
62. Jones R, Howell S, Rugman P, Casbard A, Bongard E. FAKTION; Phase 1b/2 randomised placebo controlled trial of fulvestrant +/- AZD5363 in postmenopausal women with advanced breast cancer previously treated with a 3rd generation aromatase inhibibitor. National Cancer Research Institute Cancer Conference 2016 [Abstract].
2. Cantley LC. The Phosphoinositide 3-Kinase Pathway. Science. 2002;296 (5573):1655-7.
3. Ma CX, Crowder RJ, Ellis MJ. Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors. Steroids. 2011;76(8):750-2.
4. Ciruelos Gil EM. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev. 2014;40(7):862-71.
5. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-9.
6. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer research. 2006;66(3):1500-8.
7. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26(13):1932-40.
8. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, et al. Stand up to cancer phase ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(12):1202-9.
9. Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, et al. A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor Positive Metastatic Breast Cancer. Clinical Cancer Research. 2016.
10. Ma CX, Luo J, Naughton M, Ademuyiwa FO, Suresh R, Griffith M, et al. A phase 1 trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer. Clin Cancer Res. 2015.
11. Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, et al., editors. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. San Antonio Breast Cancer Symposium; 2015; San Antonio, Texas.
12. Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997;88(4):435-7.
13. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes & development. 1999;13(22):2905-27.
14. Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America. 1987;84(14):5034-7.
15. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96(6):857-68.
16. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-74.
17. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19(1):58-71.
18. Virtakoivu R, Pellinen T, Rantala JK, Perala M, Ivaska J. Distinct roles of AKT isoforms in regulating beta1-integrin activity, migration, and invasion in prostate cancer. Mol Biol Cell. 2012;23(17):3357-69.
19. Dillon RL, Muller WJ. Distinct biological roles for the akt family in mammary tumor progression. Cancer Res. 2010;70(11):4260-4.
20. Li CW, Xia W, Lim SO, Hsu JL, Huo L, Wu Y, et al. AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation. Cancer Res. 2016;76(6):1451-62.
21. Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal. 2006;18(12):2262-71.
22. Riggio M, Perrone MC, Polo ML, Rodriguez MJ, May M, Abba M, et al. AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins. Sci Rep. 2017;7:44244.
23. Grabinski N, Mollmann K, Milde-Langosch K, Muller V, Schumacher U, Brandt B, et al. AKT3 regulates ErbB2, ErbB3 and estrogen receptor alpha expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. Cell Signal. 2014;26(5):1021-9.
24. Stottrup C, Tsang T, Chin YR. Upregulation of AKT3 Confers Resistance to the AKT Inhibitor MK2206 in Breast Cancer. Molecular cancer therapeutics. 2016;15(8):1964-74.
25. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353-60.
26. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.
27. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012;18(20):5816-28.
28. Beaver JA, Gustin JP, Yi KH, Rajpurohit A, Thomas M, Gilbert SF, et al. PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19(19):5413-22.
29. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001;276(13):9817-24.
30. Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, et al. Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res. 2001;61(16):5985-91.
31. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406-13.
32. Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res. 2006;66(7):3903-11.
33. Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 2010;12(3):R40.
34. Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol. 2005;207(2):139-46.
35. Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, et al. A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(11):2650-8.
36. Ribas R, Pancholi S, Guest SK, Marangoni E, Gao Q, Thuleau A, et al. AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo. Molecular cancer therapeutics. 2015;14(9):2035-48.
37. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Molecular cancer therapeutics. 2010;9(7):1956-67.
38. Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Molecular cancer therapeutics. 2012;11(4):873-87.
39. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(35):4688-95.
40. Yap TA, Yan L, Patnaik A, Tunariu N, Biondo A, Fearen I, et al. Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;20(22):5672-85.
41. Doi T, Tamura K, Tanabe Y, Yonemori K, Yoshino T, Fuse N, et al. Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;76(2):409-16.
42. Gonzalez-Angulo AM, Krop I, Akcakanat A, Chen H, Liu S, Li Y, et al. SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J Natl Cancer Inst. 2015;107(3).
43. Tripathy D, Chien AJ, Hylton N, Buxton MB, Ewing CA, Wallace AM, 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, (suppl; abstr 524). 2015.
44. Chien AJ, Cockerill A, Fancourt C, Schmidt E, Moasser MM, Rugo HS, et al. A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies. Breast cancer research and treatment. 2016;155(3):521-30.
45. Ma CX, Suman V, Goetz MP, Northfelt DW, Burkard ME, Ademuyiwa F, et al. A Phase II trial of neoadjuvant MK2206, an AKT inhibitor, with anastrozole in clinical stage 2 or 3 PIK3CA mutant ER positive and HER2 negative breast cancer. Clinical Cancer Research. 2017.
46. Hyman DM, Smyth L, Bedard PL, Oza A, Dean E, Armstrong A, et al. AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors. [Abstract]. In: Proceedings of the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, Massachusetts Philadelphia (PA): AACR. 2015.
47. Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, et al. AKT Inhibition in Solid Tumors With AKT1 Mutations. Journal of Clinical Oncology. 2017;35(20):2251-9.
48. Andre F, Bachelot T, Commo F, Campone M, Arnedos M, Dieras V, et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 2014;15(3):267-74.
49. Fu X, Creighton CJ, Biswal NC, Kumar V, Shea M, Herrera S, et al. Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Res. 2014;16(5):430.
50. Ren H, Guo H, Thakur A, Zhang S, Wang T, Liang Y, et al. Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells. Oncotarget. 2016.
51. Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, et al. Antitumor activity in RAS-driven tumors by blocking AKT and MEK. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(4):739-48.
52. Luey BC, May FE. Insulin-like growth factors are essential to prevent anoikis in oestrogen-responsive breast cancer cells: importance of the type I IGF receptor and PI3-kinase/Akt pathway. Mol Cancer. 2016;15:8.
53. Mata R, Palladino C, Nicolosi ML, Lo Presti AR, Malaguarnera R, Ragusa M, et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget. 2016;7(7):7683-700.
54. Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 2013;15(4):R55.
55. Brana I, Berger R, Golan T, Haluska P, Edenfield J, Fiorica J, et al. A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. Br J Cancer. 2014;111(10):1932-44.
56. Akt Inhibitor MK2206 in Treating Patients With Advanced Breast Cancer, https://clinicaltrials.gov/ct2/show/results/NCT01277757 [Accessed March 22, 2017] [
57. Wisinski KB, Tevaarwerk AJ, Burkard ME, Rampurwala M, Eickhoff J, Bell MC, et al. Phase I Study of an AKT Inhibitor (MK-2206) Combined with Lapatinib in Adult Solid Tumors Followed by Dose Expansion in Advanced HER2+ Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(11):2659-67.
58. Gupta S, Argiles G, Munster PN, Hollebecque A, Dajani O, Cheng JD, et al. A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(23):5235-44.
59. Hudis C, Swanton C, Janjigian YY, Lee R, Sutherland S, Lehman R, et al. A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors. Breast Cancer Res. 2013;15(6):R110.
60. Tamura K, Hashimoto J, Tanabe Y, Kodaira M, Yonemori K, Seto T, et al. Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016;77(4):787-95.
61. DM Hyman, L Smyth, PL Bedard, A Oza, E Dean, A Armstrong, et al. AZD5363, a catalytic pan-AKT inhibitor, in AKT1 E17K mutation positive advanced solid tumors. Presented at at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2015 [Abstract].
62. Jones R, Howell S, Rugman P, Casbard A, Bongard E. FAKTION; Phase 1b/2 randomised placebo controlled trial of fulvestrant +/- AZD5363 in postmenopausal women with advanced breast cancer previously treated with a 3rd generation aromatase inhibibitor. National Cancer Research Institute Cancer Conference 2016 [Abstract].