AKT in cancer: new molecular insights and advances in drug development

British Journal of Clinical Pharmacology

Volumn , Issue , 2016, Pages 943-956

  Mundi, Prabhjot S ^a,b   Sachdev, Jasgit ^c   McCourt, Carolyn ^d   Kalinsky, Kevin ^a,b  

^a New York Presbyterian Columbia University Medical Center   (United States)

^b Columbia University ^*  (United States)

^c HonorHealth and the Scottsdale Lincoln Health Network   (United States)

^d WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

clinical oncology; medical oncology; phosphatidylinositol 3 kinases; protein kinase B; proto oncogene proteins c AKT; proto oncogene proteins c AKT genetics; proto oncogene proteins c AKT metabolism; proto oncogene proteins c AKT physiology; signal transduction physiology

Indexed keywords

4 AMINO N [1 (4 CHLOROPHENYL) 3 HYDROXYPROPYL] 1 (7H PYRROLO[2,3 D]PYRIMIDIN 4 YL) 4 PIPERIDINECARBOXAMIDE; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; AFURESERTIB; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; UPROSERTIB;

APOPTOSIS; BREAST CANCER; CANCER THERAPY; CARCINOGENESIS; CELL DIVISION; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL (TOPIC); DRUG TARGETING; ENDOMETRIUM CANCER; ENZYME INHIBITION; GENE MUTATION; HUMAN; LUNG CANCER; MALIGNANT NEOPLASTIC DISEASE; MELANOMA; MOLECULAR BIOLOGY; MOLECULAR PATHOLOGY; NONHUMAN; ONCOGENE; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; UTERINE CERVIX CANCER;

EID: 84986260070     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.13021     Document Type: Review

References (101)

1. Vivanco I, Sawyers C. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer 2002; 7: 489–501.
2. Vara J, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/AKT signaling pathway and cancer. Cancer Treat Rev 2004; 2: 193–204.
3. Alexander SP, Mathie A, Peters JA. Guide to receptors and channels (GRAC), 5th edition. Br J Pharmacol 2011; 164 Suppl 1: S1–324.
4. Crowell JA, Steele VE, Fay JR. Targeting the AKT protein kinase for cancer chemoprevention. Mol Cancer Ther 2007; 8: 2139–48.
5. Camero A, Paramio J.The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol 2014; 4: 252.
6. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007; 7: 1261–74.
7. Blachly JS, Baiocchi RA. Targeting the PI3-kinase (PI3K), AKT, and mTOR axis in lymphoma. Br J Hematol 2014; 167: 19–32.
8. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of AKT/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.
9. Blanco-Aparicio C, Renner O, Leal JF, Carnero A. PTEN, more than the AKT pathway. Carcinogenesis 2007; 7: 1379–86.
10. Feng J, Park J, Cron P, Hess D, Hemmings BA. Identification of a PKB/AKT hydrophobic motif ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 2004; 39: 41189–96.
11. Roberts MS, Woods AJ, Dale TC, Van Der Sluijs P, Norman JC. Protein kinase B/AKT acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol Cell Bio 2004; 24: 1505–15.
12. Huang J, Manning BD. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412: 179–90.
13. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M. Cross-talk between AKT, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 2002; 21: 1299–303.
14. Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/AKT pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 2001; 98: 11598–1603.
15. Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. AKT phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Bio 2001; 3: 893–901.
16. Ko FC, Chan LK, Tung EK, Lowe SW, Ng IO, Yam JW. AKT phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis. Gastroenterology 2010; 139: 1397–1407.
17. Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors: regulation by AKT and 14-3-3 proteins. Mol Cell Res 2011; 1813: 1938–45.
18. Ni D, Ma X, Li HZ, Gao Y, Li XT, Zhang Y, et al. Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasis-free survival of patients with clear cell renal cell carcinoma. Clin Can Res 2014; 20: 1779–90.
19. Du K, Montminy M. CREB is a regulatory target for the protein kinase AKT/PKB. J Biol Chem 1998; 49: 32377–9.
20. Hussain AR, Ahmed SO, Ahmed M, Khan OS, Al Abdulmohsen S, Platanias LC, et al. Cross-talk between NFkB and the PI3-kinase/AKT pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis. PLoS One 2012; 7: e39945. doi: 10.1371/journal.pone.0039945.
21. Gonzalez E, McGraw TE. The AKT kinases: isoform specificity in metabolism and cancer. Cell Cycle 2009; 8: 2502–8.
22. Ji W, Chen X, Lv J, Wang M, Ren S, Yuan B, et al. Liraglutide exerts antidiabetic effect via PTP1B and PI3K/AKT2 signaling pathway in skeletal muscle of KKAy mice. Int J Endocrinol 2014; 2014: 312452. doi: 10.1155/2014/312452.
23. Paz-Ares L, Blanco-Aparicio C, Garcia-Carbonero R, Camero A. Inhibiting PI3K as a therapeutic strategy against cancer. Clin Transl Oncol 2009; 11: 572–9.
24. Dummler B, Tschopp O, Hynx D, Yang ZZ, Dimhofer S, Hemmings BA. Life with a single isoform of AKT: mice lacking AKT2 and AKT3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol 2006; 26: 8042–51.
25. Inoue K, Fry EA, Taneja P. Recent progress in mouse models for tumor suppressor genes and its implications in human cancer. Clin Med Insights Oncol 2013; 7: 103–22.
26. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Carco Barrantes, I, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 1998; 8: 1169–78.
27. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19: 348–55.
28. Hutchinson J, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of AKT (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol Cell Biol 2001; 21: 2203–12.
29. Ackler S, Ahmad S, Tobias C, Johnson MD, Glazer RI. Delayed mammary gland involution in MMTV-AKT1 transgenic mice. Oncogene 2002; 21: 198–206.
30. Schwertfeger KL, Richert MM, Anderson SM. Mammary gland involution is delayed by activated AKT in transgenic mice. Mol Endocrinol 2001; 15: 867–81.
31. Blanco-Aparicio C, Canamero M, Cecilia Y, Pequeno B, Renner O, Ferrer I, et al. Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models. PLoS One 2010; 5: e9305. doi: 10.1371/journal.pone.0009305.
32. Deng CX, Brodie SG. Knockout mouse models and mammary tumorigenesis. Semin Cancer Biol 2001; 11: 387–94.
33. Dunbar ME, Wysolmerski JJ. Mammary ductal and alveolar development: lesson learned from genetically manipulated mice. Microsc Res Tech 2001; 52: 163–70.
34. Segrelles C, Moral M, Lara MF, Ruiz S, Santo M, Leis H, et al. Molecular determinants of AKT-induced keratinocyte transformation. Oncogene 2006; 25: 1174–85.
35. Segrelles C, Lu J, Hammann B, Santos M, Moral M, Cascallana JL, et al. Deregulated activity of AKT in epithelial basal cells induces spontaneous tumors and heightened sensitivity to skin carcinogenesis. Cancer Res 2007; 67: 10879–88.
36. Moral M, Segrelles C, Lara MF, Martinez-Cruz AB, Lorz C, Santos M, et al. AKT activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma. Cancer Res 2009; 69: 1099–108.
37. Majumder PK, Yeh JJ, George DJ, Febbo PG, Jum J, Zue Q, et al. Prostate intraepithelial neoplasia induced by prostate restricted AKT activation: the MPAKT model. Proc Natl Acad Sci U S A 2003; 100: 7841–6.
38. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and AKT in neural progenitors induces glioblastoma formation in mice. Nat Genet 2000; 25: 55–7.
39. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502: 333–9.
40. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase AKT/PKB. Exp Cell Res 1999; 253: 210–29.
41. Liaw D, Marsh DJ, Li, J, Dahia, PL, Wang, S, Zheng, Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16: 64–7.
42. Boyault S, Drouet Y, Navarro C, Bachelot T, Lasset C, Treilleux I, et al. Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes. Breast Cancer Res Treat 2012; 132: 29–39.
43. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 2008; 68: 6084–91.
44. Kumar A, Purohit R. Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain. PLoS One 2013; 8: e64364. doi: 10.1371/journal.pone.0064364.
45. Askham JM, Platt F, Chambers PA, Snowden H, Taylor CF, Knowles MA. AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K. Oncogene 2010; 29: 150–5.
46. Parikh C, Janakiraman V, Wu W, Foo CK, Kljavin NM, Chaudhuri S, et al. Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers. Proc Natl Acad Sci 2012; 109: 19368–73.
47. Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 2009; 15: 7538–546.
48. Park ES, Rabinovsky R, Carey M, Hennessy BT, Agarwal R, Liu W, et al. Integrative analysis of proteomic signatures, mutations, and drug responsiveness in the NCI 60 cancer cell line set. Mol Cancer Ther 2010; 9: 257–67.
49. Kim MS, Jeong EG, Yoo NJ, Lee SH. Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br J Cancer 2008; 98: 1533–5.
50. Perou C; Cancer Genome Atlas Network. Comprehensive portraits of human breast tumors. Nature 2012; 490: 61–70.
51. Landgraf KE, Pilling C, Falke JJ. Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain. Biochemistry 2008; 47: 12260–9.
52. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012; 486: 400–4.
53. Yi KH, Axtmayer J, Gustin JP, Rajpurohit A, Lauring J. Functional analysis of non-hotspot AKT1 mutants found in human breast cancers identifies novel driver mutations: implications for personalized medicine. Oncotarget 2013; 4: 29–34.
54. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005; 24: 7455–64.
55. Chan CH, Jo U, Kohrman A, Rezaeian AH, Chou PC, Logothetis C, et al. Posttranslational regulation of AKT in human cancer. Cell and Bioscience 2014; 4: 59.
56. Ahmed NN, Franke TF, Bellacosa A, Datta K, Gonzalez-Portal ME, Taguchi T, et al. The proteins encoded by c-AKT and v-AKT differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 1993; 8: 1957–63.
57. Yang WK, Wu CY, Wu J, Lin HK. Regulation of AKT signaling activation by ubiquitination. Cell Cycle 2010; 9: 487–97.
58. Sale EM, Sale GJ. Protein kinase B: signaling roles and therapeutic targets. Cell Mol Life Sci 2008; 65: 113–27.
59. Shao Y, Aplin AE. AKT3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res 2010; 70: 6670–81.
60. West KA, Linnoila IR, Belinsky SA, Harris CC, Dennis PA. Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3′-kinase/AKT pathway in vitro and in vivo. Cancer Res 2004; 64: 446–51.
61. Chun KH, Kosmeder JW, Sun S, Pezzuto JM, Lotan R, Hong WK, et al. Effects of deguelin on the phosphatidylinositol 3-kinase/AKT pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 2003; 95: 291–302.
62. Bose S, Chandran S, Mirocha JM, Bose N. The AKT pathway in human breast cancer: a tissue-array-based analysis. Mod Pathol 2006; 19: 238–45.
63. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10: 594–601.
64. Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, et al. Immunohistochemical demonstration of phospho-AKT in high Gleason grade prostate cancer. Clin Cancer Res 2002; 8: 1168–71.
65. Xin L, Teitell MA, Lawson DA, Kwon A, Mellinghoff IK, Witte ON. Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc Natl Acad Sci U S A 2006; 103: 7789–94.
66. Majumder PK, Sellers WR. AKT-regulated pathways in prostate cancer. Oncogene 2005; 24: 7465–74.
67. Dai DL, Martinka M, Li G. Prognostic significance of activated AKT expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol 2005; 23: 1473–82.
68. Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, et al. Deregulated AKT3 activity promotes development of malignant melanoma. Cancer Res 2004; 64: 7002–10.
69. Bedogni B, Welford SM, Cassarino DS, Nickoloff BJ, Giaccia AJ, Powell MB. The hypoxic microenvironment of the skin contributes to AKT-mediated melanocyte transformation. Cancer Cell 2005; 8: 443–54.
70. McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006; 46: 249–79.
71. Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, et al. Landscape of genomic alterations in cervical carcinomas. Nature 2014; 506: 371–5.
72. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497: 67–73.
73. Du CX, Wang Y. Expression of P-AKT, NFkappaB and their correlation with human papillomavirus infection in cervical carcinoma. Eur J Gynaecol Oncol 2012; 33: 274–7.
74. Gupta AK, Lee JH, Wilke WW, Quon H, Smith G, Maity A, et al. Radiation response in two HPV-infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKT. Int J Radiat Oncol Biol Phys 2009; 74: 928–33.
75. Grabinski N, Mollmann K, Milde-Langosch K, Müller V, Schumacher U, Brandt B, et al. AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. Cell Signal 2014; 26: 1021–9.
76. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007.
77. Geuna E, Milani A, Martinello R, Aversa C, Valabrega G, Scaltriti M, et al. Buparlisib, an oral pan-PI3K inhibitor for the treatment of breast cancer. Expert Opin Investig Drugs 2015; 24: 421–31.
78. Baselga J. PI3K inhibitor improves PFS in BELLE-2 trial. Cancer Discov 2016; 6: 115–6. (San Antonio Breast Cancer Symposium 2015 abstract and oral session).
79. Dienstmann R, Rodon J, Serra V, Tabernero J. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 2014; 13: 1021–31.
80. Pal SK, Reckamp K, Yu H, Figlin RA. AKT inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010; 19: 1355–66.
81. Lindsley CW, Barnett SF, Yaroschak M, Bilodeau MT, Layton ME. Recent progress in the development of ATP-competitive and allosteric AKT kinase inhibitors. Curr Top Med Chem 2007; 7: 1349–63.
82. Crul M, Rosing H, de Klerk GJ, Dubbelman R, Traiser M, Reichert S, et al. Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 2002; 38: 1615–21.
83. Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT, Hermann RC, et al. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 2011; 29: 4394–400.
84. Bendell JC, Ervin TJ, Senzer NN, Richards DA, Firdaus I, Lockhart AC, et al. Results of the X-PECT study: a phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). J Clin Oncol 2012; American Society of Clinical Oncology Meeting Abstract.
85. Jakubowiak AJ, Richardson PG, Zimmerman T, Alsina M, Kaufman JL, Kandarpa M, et al. Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study. Br J Haematol 2012; 158: 472–80.
86. Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, et al. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. J Clin Oncol 2011; 29: 4243–9.
87. 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. Mol Cancer Ther 2010; 9: 1956–67.
88. Kalinsky KM, Sparano JA, Andreopoulou E, Taback B, Wiechmann LS, Feldman SM, et al. Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer. J Clin Oncol 2014, American Society of Clinical Oncology Meeting Abstract.
89. Tolcher AW, Yap TA, Fearen I, Taylor A, Carpenter C, Brunetto AT, et al. A phase I study of MK-2206, an oral potent allosteric AKT inhibitor (AKTi), in patients (pts) with advanced solid tumor (ST). J Clin Oncol 2009, American Society of Clinical Oncology Meeting Abstract.
90. 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: R110. doi: 10.1186/bcr3577.
91. Oki Y, Fanale M, Romaguera J, Fayad L, Fowler N, Copeland A, et al. Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma. Br J Haematol 2015; 171: 463–70.
92. Ma CX1, Sanchez C2, Gao F3, Crowder R4, Naughton M5, 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. Clin Cancer Res 2016; 22: 2650–8.
93. Ramanathan RK, McDonough SL, Kennecke HF, Iqbal S, Baranda JC, Seery TE, et al. Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: a SWOG cooperative group trial (S1005). Cancer 2015; 121: 2193–7.
94. Lara PN, Longmate J, Mack PC, Kelly K, Socinski MA, Salgia R, et al. Phase II study of the AKT inhibitor MK-2206 plus erlotinib in patients with advanced non-small cell lung cancer who previously progressed on erlotinib. Clin Cancer Res 2015; 21: 4321–6.
95. Do K, Speranza G, Bishop R, Khin S, Rubinstein L, Kinders RJ, et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest New Drugs 2015; 33: 720–8.
96. Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol 2015; 75: 183–9.
97. Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith, DA, Brigandi, RA, et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood 2014; 124: 2190–5.
98. Toren P, Kim S, Cordonnier T, Crafter C, Davies BR, Fazli L, et al. Combination AZD5363 with enzalutamide significantly delays enzalutamide-resistant prostate cancer in preclinical models. Eur Urol 2015; 67: 986–90.
99. 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. Mol Cancer Ther 2012; 11: 873–87.
100. Banerji U. A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in PIK3CA mutant breast and gynecological cancers. J Clin Oncol 2015, American Society of Clinical Oncology Meeting Abstract.
101. Algazi AP, Muthukumar AH, Obrien K, Lencioni A, Tsai KK, Kadafour M, et al. Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma. J Clin Oncol 2015, American Society of Clinical Oncology Meeting Abstract.