Targeting AKT for cancer therapy

References

• DeSantis C, Siegel R, Bandi P, et al. Breast cancer statistics, 2011. CA Cancer J Clin. 2011 Nov - Dec;61(6):409–418. PubMed PMID: WOS:000297106500006; English.
   PubMed Web of Science ®Google Scholar
• Stewart SL, Harewood R, Matz M, et al. Disparities in ovarian cancer survival in the United States (2001–2009): findings from the CONCORD-2 study. Cancer-Am Cancer Soc. 2017 Dec;15(123):5138–5159. PubMed PMID: WOS:000417216800013; English.
   PubMed Web of Science ®Google Scholar
• Fan WM, Chang JJ, Fu PF. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Future Med Chem. 2015;7(12):1511–1519. PubMed PMID: WOS:000360939800006; English.
   PubMed Web of Science ®Google Scholar
• Monk BJ, Coleman RL. Changing the paradigm in the treatment of platinum-sensitive recurrent ovarian cancer from platinum doublets to nonplatinum doublets and adding antiangiogenesis compounds. Int J Gynecol Cancer. 2009 Dec;19:S63–S67. PubMed PMID: WOS:000273151800013; English.
   PubMed Web of Science ®Google Scholar
• Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233–247. PubMed PMID: WOS:000287956900017; English.
   PubMed Web of Science ®Google Scholar
• van Zyl B, Tang D, Bowden NA. Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. Endocr Relat Cancer. 2018 May;25(5):R303–R318. PubMed PMID: WOS:000430734900004; English.
   PubMed Web of Science ®Google Scholar
• Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995 Aug 22;64(4):280–285. PubMed PMID: 7657393.
   PubMed Web of Science ®Google Scholar
• Dahl E, Sadr-Nabavi A, Klopocki E, et al. Systematic identification and molecular characterization of genes differentially expressed in breast and ovarian cancer. J Pathol. 2005 Jan;205(1):21–28. PubMed PMID: WOS:000225919600003; English.
   PubMed Web of Science ®Google Scholar
• Ma CX. The PI3K pathway as a therapeutic target in breast cancer. Am J Hematol-Oncol. 2015 Mar;11(3):23–29. PubMed PMID: WOS:000420385800005; English.
   Google Scholar
• Mabuchi S, Kuroda H, Takahashi R, et al. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol. 2015 Apr;137(1):173–179. PubMed PMID: WOS:000353079600028; English.
   PubMed Web of Science ®Google Scholar
• Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005 Sep;8;3:179–183. PubMed PMID: WOS:000232199900005; English.
   PubMed Web of Science ®Google Scholar
• Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 2001 Aug;114(16):2903–2910. PubMed PMID: WOS:000170757400003; English.
   PubMed Web of Science ®Google Scholar
• Steelman LS, Stadelman KM, Chappell WH, et al. Akt as a therapeutic target in cancer. Expert Opin Ther Tar. 2008 Sep;12(9):1139–1165. PubMed PMID: WOS:000258856500007; English.
   PubMed Web of Science ®Google Scholar
• Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017 Apr 20;169(3):381–405. PubMed PMID: WOS:000399560600005; English.
   PubMed Web of Science ®Google Scholar
• Mundi PS, Sachdev J, McCourt C, et al. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016 Oct;82(4):943–956. PubMed PMID: 27232857; PubMed Central PMCID: PMCPMC5137819.
   PubMed Web of Science ®Google Scholar
• Cheon DJ, Orsulic S. Mouse models of cancer. Annu Rev Pathol -Mech. 2011;6:95–119. PubMed PMID: WOS:000288922800005; English.
   PubMed Web of Science ®Google Scholar
• Singh M, Johnson L. Using genetically engineered mouse models of cancer to aid drug development: an industry perspective. Clin Cancer Res. 2006 Sep 15;12(18):5312–5328. PubMed PMID: WOS:000240714400013; English.
   PubMed Web of Science ®Google Scholar
• Arcaro A, Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics. 2007 Aug;8;5:271–306. PubMed PMID: WOS:000251734700001; English.
   PubMed Web of Science ®Google Scholar
• Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004 Apr;15(2):177–182. PubMed PMID: WOS:000220312500005; English.
   PubMed Web of Science ®Google Scholar
• Testa JR, Bellacosa A. Commentary - AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):10983–10985. PubMed PMID: WOS:000171237100003; English.
   PubMed Web of Science ®Google Scholar
• Wang J, Zhao W, Guo H, et al. AKT isoform-specific expression and activation across cancer lineages. BMC Cancer. 2018 Jul 16;18(1):742. PubMed PMID: 30012111; PubMed Central PMCID: PMCPMC6048698.
   PubMed Web of Science ®Google Scholar
• Hanada M, Feng JH, Hemmings BA. Structure, regulation and function of PKB/AKT - a major therapeutic target. Bba-Proteins Proteom. 2004 Mar 11;1697(1–2):3–16. PubMed PMID: WOS:000220446500002; English.
   PubMed Web of Science ®Google Scholar
• Hemmings BA. Structure, regulation and function of PKB/Akt - A major therapeutic target. Cell Mol Biol Lett. 2003;8(2a):527–527. PubMed PMID: WOS:000184166400011; English.
   Web of Science ®Google Scholar
• Barnett SF, Defeo-Jones D, Fu S, et al. Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem J. 2005 Jan 15;385(Pt 2):399–408. PubMed PMID: 15456405; PubMed Central PMCID: PMCPMC1134710.
   PubMed Web of Science ®Google Scholar
• Dummler B, Hemmings BA. Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans. 2007 Apr;35(Pt 2):231–235. PubMed PMID: 17371246.
   PubMed Web of Science ®Google Scholar
• Zhou GL, Tucker DF, Bae SS, et al. Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J Biol Chem. 2006 Nov 24;281(47):36443–36453. PubMed PMID: 17012749.
   PubMed Web of Science ®Google Scholar
• Easton RM, Cho H, Roovers K, et al. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol. 2005 Mar;25(5):1869–1878. PubMed PMID: 15713641; PubMed Central PMCID: PMCPMC549378.
   PubMed Web of Science ®Google Scholar
• Liao Y, Hung MC. Physiological regulation of Akt activity and stability. Am J Transl Res. 2010;2(1):19–42. PubMed PMID: WOS:000208694000002; English.
   PubMed Web of Science ®Google Scholar
• Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. Febs Lett. 2003 Jul 3;546(1):108–112. PubMed PMID: WOS:000183970500018; English.
   PubMed Web of Science ®Google Scholar
• Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha. Curr Biol. 1997 Apr 1;7(4):261–269. PubMed PMID: WOS:A1997WV36600025; English.
   PubMed Web of Science ®Google Scholar
• Conus NM, Hannan KM, Cristiano BE, et al. Direct identification of tyrosine 474 as a regulatory phosphorylation site for the Akt protein kinase. J Bio Chem. 2002 Oct 11;277(41):38021–38028. PubMed PMID: WOS:000178529600008; English.
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005 Feb 18;307(5712):1098–1101. PubMed PMID: WOS:000227197300045; English.
   PubMed Web of Science ®Google Scholar
• Feng J, Park J, Cron P, et al. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem. 2004 Sep 24;279(39):41189–41196. PubMed PMID: 15262962.
   PubMed Web of Science ®Google Scholar
• Gray CW, Coster ACF. Crosstalk in transition: the translocation of Akt. J Math Biol. 2018 Oct 9. DOI:10.1007/s00285-018-1297-8. PubMed PMID: 30306249.
   PubMed Web of Science ®Google Scholar
• O’Neill AK, Niederst MJ, Newton AC. Suppression of survival signalling pathways by the phosphatase PHLPP. Febs J. 2013 Jan;280(2):572–583. PubMed PMID: 22340730; PubMed Central PMCID: PMCPMC3770140.
   PubMed Web of Science ®Google Scholar
• Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005 Apr 1;18(1):13–24. PubMed PMID: 15808505.
   PubMed Web of Science ®Google Scholar
• Altomare DA, Khaled AR. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem. 2012 Aug;19(22):3748–3762. PubMed PMID: WOS:000306494500011; English.
   PubMed Web of Science ®Google Scholar
• Jacinto E, Facchinetti V, Liu D, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006 Oct 6;127(1):125–137. PubMed PMID: WOS:000241445800019; English.
   PubMed Web of Science ®Google Scholar
• Li XJ, Leem SH, Park MH, et al. Regulation of YAP through an Akt-dependent process by 3, 3 ‘-diindolylmethane in human colon cancer cells. Int J Oncol. 2013 Dec;43(6):1992–1998. PubMed PMID: WOS:000330225800030; English.
   PubMed Web of Science ®Google Scholar
• Xu Q, Liu LZ, Qian X, et al. MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res. 2012 Jan;40(2):761–774. PubMed PMID: WOS:000299095900032; English.
   PubMed Web of Science ®Google Scholar
• Morrison DK. The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol. 2009 Jan;19(1):16–23. PubMed PMID: 19027299; PubMed Central PMCID: PMCPMC3073487.
   PubMed Web of Science ®Google Scholar
• Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997 Oct 17;91(2):231–241. PubMed PMID: WOS:A1997YC35000010; English.
   PubMed Web of Science ®Google Scholar
• Qi XJ, Wildey GM, Howe PH. Evidence that Ser(87) of Bim(EL) is phosphorylated by Akt and regulates BimEL apoptotic function. J Bio Chem. 2006 Jan 13;281(2):813–823. PubMed PMID: WOS:000234447200019; English.
   PubMed Web of Science ®Google Scholar
• Sangawa A, Shintani M, Yamao N, et al. Phosphorylation status of Akt and caspase-9 in gastric and colorectal carcinomas. Int J Clin Exp Patho. 2014;7(6):3312–3317. PubMed PMID: WOS:000338770500062; English.
   PubMed Web of Science ®Google Scholar
• Zhang XB, Tang NM, Hadden TJ, et al. Akt, FoxO and regulation of apoptosis. Bba-Mol Cell Res. 2011 Nov;1813(11):1978–1986. PubMed PMID: WOS:000295766200009; English.
   PubMed Web of Science ®Google Scholar
• Ogawara Y, Kishishita S, Obata T, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Bio Chem. 2002 Jun 14;277(24):21843–21850. PubMed PMID: WOS:000176286000094; English.
   PubMed Web of Science ®Google Scholar
• Park S, Kim D, Dan HC, et al. Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53. J Bio Chem. 2012 Mar 30;287(14):11151–11163. PubMed PMID: WOS:000302780100043; English.
   PubMed Web of Science ®Google Scholar
• Park S, Kim D, Dan HC, et al. Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53 (vol 287, pg 11151, 2012). J Bio Chem. 2016 Oct 21;291(43):22852–22852. PubMed PMID: WOS:000386760600051; English.
   PubMed Web of Science ®Google Scholar
• Shi Y, Liu X, Han EK, et al. Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. Neoplasia. 2005 Nov;7(11):992–1000. PubMed PMID: 16331885; PubMed Central PMCID: PMCPMC1502019.
   PubMed Web of Science ®Google Scholar
• Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007 Jul 26;448(7152):439–444. PubMed PMID: 17611497.
   PubMed Web of Science ®Google Scholar
• Kroeger PT, Drapkin R. Pathogenesis and heterogeneity of ovarian cancer. Curr Opin Obstet Gyn. 2017 Feb;29(1):26–34. PubMed PMID: WOS:000391954100005; English.
   PubMed Web of Science ®Google Scholar
• Arboleda MJ, Lyons JF, Kabbinavar FF, et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 2003 Jan 1;63(1):196–206. PubMed PMID: 12517798.
   PubMed Web of Science ®Google Scholar
• Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61–70. PubMed PMID: 23000897; PubMed Central PMCID: PMCPMC3465532.
   PubMed Web of Science ®Google Scholar
• Carmona FJ, Montemurro F, Kannan S, et al. AKT signaling in ERBB2-amplified breast cancer. Pharmacol Ther. 2016 Feb;158:63–70. PubMed PMID: 26645663; PubMed Central PMCID: PMCPMC4747800.
   PubMed Web of Science ®Google Scholar
• Cristiano BE, Chan JC, Hannan KM, et al. A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition. Cancer Res. 2006 Dec 15;66(24):11718–11725. PubMed PMID: WOS:000242915600027; English.
   PubMed Web of Science ®Google Scholar
• Bhutani J, Sheikh A, Niazi AK. Akt inhibitors: mechanism of action and implications for anticancer therapeutics. Infect Agent Cancer. 2013 Dec;13:8. PubMed PMID: WOS:000329092000001; English.
   Google Scholar
• Fortier AM, Asselin E, Cadrin M. Functional specificity of Akt isoforms in cancer progression. Biomol Concepts. 2011 Apr 1;2(1–2):1–11. PubMed PMID: 25962016.
   PubMedGoogle Scholar
• Blake JF, Xu R, Bencsik JR, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt Inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012 Sep 27;55(18):8110–8127. PubMed PMID: WOS:000309153500015; English.
   PubMed Web of Science ®Google Scholar
• Lin J, Sampath D, Nannini MA, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760–1772. PubMed PMID: WOS:000316996900015; English.
   PubMed Web of Science ®Google Scholar
• Saura C, Roda D, Rosello S, et al. A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov. 2017 Jan 7;(1):102–113. DOI:10.1158/2159-8290.Cd-16-0512. PubMed PMID: WOS:000396017700025; English.
   PubMed Web of Science ®Google Scholar
• Isakoff SJ, Infante JR, Juric D, et al. Phase Ib dose-escalation study of the Akt Inhibitor Ipatasertib (Ipat) with Paclitaxel (P) in Patients (Pts) with advanced solid tumors. Ann Oncol. 2014 Sep; 25:iv148. PubMed PMID: WOS:000346901000204; English.
   PubMed Web of Science ®Google Scholar
• Kim SB, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1360–1372. PubMed PMID: WOS:000411843500052; English.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther. 2011 Jun;10(6):1093–1101. PubMed PMID: 21490305; PubMed Central PMCID: PMCPMC3112276.
   PubMed Web of Science ®Google Scholar
• Addie M, Ballard P, Buttar D, et al. Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem. 2013 Mar 14;56(5):2059–2073. PubMed PMID: WOS:000316308300023; English.
   PubMed Web of Science ®Google Scholar
• Davies BR, Greenwood H, Dudley P, 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 Apr;11(4):873–887. PubMed PMID: WOS:000302809200008; English.
   PubMed Web of Science ®Google Scholar
• Davies BR, Guan N, Logie A, et al. Tumors with AKT1(E17K) mutations are rational targets for single agent or combination therapy with AKT inhibitors. Mol Cancer Ther. 2015 Nov;14(11):2441–2451. PubMed PMID: WOS:000364592000004; English.
   PubMed Web of Science ®Google Scholar
• Hyman DM, Smyth LM, Donoghue MTA, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017 Jul 10;35(20):2251–+. PubMed PMID: WOS:000404985200007; English.
   Web of Science ®Google Scholar
• Zimmer K, Kocher F, Spizzo G, et al. Capivasertib active against AKT1-mutated cancers. Cancer Discov. 2019;9(1):OF7–OF7.
   Google Scholar
• Smyth LM, Oliveira M, Ciruelos E, et al. AZD5363 in combination with fulvestrant in AKT1-mutant ER-positive metastatic breast cancer. Cancer Res. 2018 Feb;78(4):774–780. PubMed PMID: WOS:000425489402066; English.
   Google Scholar
• Vicier C, Isambert N, Dalenc F, et al. TAKTIC: A prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients. J Clin Oncol. 2019;37(15_suppl):1091–1091.
   Web of Science ®Google Scholar
• Schmid P, Abraham J, Chan S, et al. AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial. J Clin Oncol. 2018 May 20;36(15). DOI:10.1200/JCO.2018.36.15_suppl.1007. PubMed PMID: WOS:000442916001030; English.
   PubMed Web of Science ®Google Scholar
• Westin S, Litton J, Williams R, et al. Phase I expansion of olaparib (PARP inhibitor) and AZD5363 (AKT inhibitor) in recurrent ovarian, endometrial and triple negative breast cancer. Ann Oncol. 2017 Sep; 28:130. PubMed PMID: WOS:000411324001051; English.
   PubMed Web of Science ®Google Scholar
• Lapierre JM, Eathiraj S, Vensel D, et al. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): an orally bioavailable, selective, and potent allosteric AKT inhibitor. J Med Chem. 2016 Jul 14;59(13):6455–6469. PubMed PMID: WOS:000379989800034; English.
   PubMed Web of Science ®Google Scholar
• Yu Y, Savage RE, Eathiraj S, et al. Targeting AKT1-E17K and the PI3K/AKT pathway with an allosteric AKT inhibitor, ARQ 092. Plos One. 2015 Oct 15;10(10). DOI:10.1371/journal.pone.0140479. PubMed PMID: WOS:000363184600067; English.
   Web of Science ®Google Scholar
• Tolcher A, Harb W, Sachdev J, et al. Results from a phase 1 study of ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. Eur J Cancer. 2015 Sep;51:S66–S66. PubMed PMID: WOS:000361887400207; English.
   Web of Science ®Google Scholar
• Abbadessa G, Yu Y, Eathiraj S, et al. Abstract B181: association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients. Mol Cancer Ther. 2015;14(12 Supplement 2):B181–B181.
   Google Scholar
• Lakhani N, Tolcher AW, Rasco DW, et al. Results of a phase Ib study of ARQ 092 in combination with carboplatin (C) plus paclitaxel (P), or with P in patients (pts) with solid tumors. J Clin Oncol. 2017 May 20;35. DOI:10.1200/JCO.2017.35.15_suppl.2524. PubMed PMID: WOS:000411895704127; English.
   Web of Science ®Google Scholar
• Pant S, Subbiah V, Rodon J, et al. Abstract CT024: results of a phase I dose escalation study of ARQ 751 in adult subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations. Cancer Res. 2018;78(13Supplement):CT024–CT024.
   Google Scholar
• Lindhurst MJ, Yourick MR, Yu Y, et al. Repression of AKT signaling by ARQ 092 in cells and tissues from patients with proteus syndrome. Sci Rep-Uk. 2015 Dec 11;5. DOI:10.1038/srep17162. PubMed PMID: WOS:000366183900001; English.
   PubMed Web of Science ®Google Scholar
• Dumble M, Crouthamel MC, Zhang SY, et al. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014;9(6):e100880. PubMed PMID: 24978597; PubMed Central PMCID: PMCPMC4076210.
   PubMed Web of Science ®Google Scholar
• Spencer A, Yoon SS, Harrison SJ, et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014 Oct 2;124(14):2190–2195. PubMed PMID: WOS:000342763900011; English.
   PubMed Web of Science ®Google Scholar
• Blagden SP, Gabra H, Hamilton AL, et al. Phase I/II dose-escalation and expansion study of afuresertib plus carboplatin and paclitaxel in recurrent ovarian cancer. J Clin Oncol. 2016 May 20;34(15). DOI:10.1200/JCO.2016.34.15_suppl.2551. PubMed PMID: WOS:000404665403150; English.
   Web of Science ®Google Scholar
• Tolcher AW, Patnaik A, Papadopoulos KP, 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 Chemoth Pharm. 2015 Jan;75(1):183–189. PubMed PMID: WOS:000347153200019; English.
   PubMed Web of Science ®Google Scholar
• Aghajanian C, Bell-McGuinn KM, Burris HA 3rd, et al. A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors. Invest New Drugs. 2018 Dec;36(6):1016–1025. PubMed PMID: 29611022; PubMed Central PMCID: PMCPMC6170741.
   PubMed Web of Science ®Google Scholar
• Sangai T, Akcakanat A, Chen HQ, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res. 2012 Oct 15;18(20):5816–5828. PubMed PMID: WOS:000311908500033; English.
   PubMed Web of Science ®Google Scholar
• Lu W, Defeo-Jones D, Davis L, et al. In vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor. Cancer Res. 2009 May1; 69:3714. PubMed PMID: WOS:000209702706029; English.
   Web of Science ®Google Scholar
• Myers AP, Broaddus R, Makker V, et al. Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC). J Clin Oncol. 2013;31(15_suppl):5524–5524.
   Web of Science ®Google Scholar
• Xing Y, Lin NU, Maurer MA, et al. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Res. 2019 Jul 05;21(1):78.
   PubMed Web of Science ®Google Scholar
• Stottrup C, Tsang T, Chin YR. Upregulation of AKT3 confers resistance to the AKT inhibitor MK2206 in breast cancer. Mol Cancer Ther. 2016 Aug;15(8):1964–1974. PubMed PMID: 27297869; PubMed Central PMCID: PMCPMC4975650.
   PubMed Web of Science ®Google Scholar
• Kumler I, Tuxen MK, Nielsen DL. A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev. 2014 Mar;40(2):259–270. PubMed PMID: WOS:000329274700007; English.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Angulo AM, Krop I, Akcakanat A, et al. SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J Natl Cancer Inst. 2015 Mar;107(3). DOI:10.1093/jnci/dju493. PubMed PMID: WOS:000351297400013; English.
   PubMedGoogle Scholar
• Tripathy D, Chien AJ, Hylton N, et al. Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206: graduation results from the I-SPY 2 trial. J Clin Oncol. 2015 May 20;33(15). PubMed PMID: WOS:000358036901131; English.
   PubMed Web of Science ®Google Scholar
• Kalinsky K, Sparano JA, Zhong X, et al. Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York cancer consortium trial. Clin Transl Oncol. 2018 Nov;20(11):1474–1483. PubMed PMID: 29736694; PubMed Central PMCID: PMCPMC6222014.
   PubMed Web of Science ®Google Scholar
• Ma CX, Suman V, Goetz MP, et al. A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer. Clin Cancer Res. 2017 Nov 15;23(22):6823–6832. PubMed PMID: 28874413.
   PubMed Web of Science ®Google Scholar
• Akcakanat A, Meric-Bernstam F. MK-2206 window of opportunity study in breast cancer. Ann Transl Med. 2018 Nov;6(Suppl 1):S57. PubMed PMID: 30613632; PubMed Central PMCID: PMCPMC6291614 grants from and Novartis, AstraZeneca, Taiho, Genentech, Calithera, Debio International Group, Bayer, PUMA, Aileron, Jounce, CytoMx, Effector, Zymeworks, Curis, and Pfizer and is a consultant/advisory board member for Dialecta, Sumitomo Dainippon, Pieris Pharmaceuticals, Darwin Health, Samsung Bioepis, Aduro, and Spectrum, OrigiMed, Debiopharm International, Inflection Biosciences, Xencor, and Genentech. The other author has no conflicts of interest to declare.
   PubMed Web of Science ®Google Scholar
• Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006 May 15;107(10):4053–4062. PubMed PMID: WOS:000237584500042; English.
   PubMed Web of Science ®Google Scholar
• Leighl NB, Dent S, Clemons M, et al. A phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Tr. 2008 Mar;108(1):87–92. PubMed PMID: WOS:000253198600009; English.
   PubMed Web of Science ®Google Scholar
• Fu SQ, Hennessy BT, Ng CS, et al. Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. Gynecol Oncol. 2012 Jul;126(1):47–53. PubMed PMID: WOS:000305878400010; English.
   PubMed Web of Science ®Google Scholar
• Politz O, Siegel F, Barfacker L, et al. BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models. Int J Cancer. 2017 Jan 15;140(2):449–459. PubMed PMID: WOS:000390703600021; English.
   PubMed Web of Science ®Google Scholar
• Berndt N, Yang H, Trinczek B, et al. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 2010 Nov;17(11):1795–1804. PubMed PMID: WOS:000282726700013; English.
   PubMed Web of Science ®Google Scholar
• Dieterle A, Orth R, Daubrawa M, et al. The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. Int J Cancer. 2009 Aug 15;125(4):932–941. PubMed PMID: WOS:000268287700024; English.
   PubMed Web of Science ®Google Scholar
• Evangelisti C, Ricci F, Tazzari P, et al. Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia. J Cell Physiol. 2011 Mar;226(3):822–831. PubMed PMID: WOS:000287258100027; English.
   PubMed Web of Science ®Google Scholar
• Kim R, Yamauchi T, Husain K, et al. Triciribine phosphate monohydrate, an AKT inhibitor, enhances gemcitabine activity in pancreatic cancer cells. Anticancer Res. 2015 Sep;35(9):4599–4604. PubMed PMID: WOS:000359311000006; English.
   PubMed Web of Science ®Google Scholar
• Garrett CR, Coppola D, Wenham RM, et al. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drug. 2011 Dec;29(6):1381–1389. PubMed PMID: WOS:000294824200027; English.
   PubMed Web of Science ®Google Scholar
• Sampath D, Malik A, Plunkett W, et al. Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies. Leukemia Res. 2013 Nov;37(11):1461–1467. PubMed PMID: WOS:000326269500014; English.
   PubMed Web of Science ®Google Scholar
• Mimura N, Ohguchi H, Cirstea D, et al. TAS-117, a novel selective Akt inhibitor demonstrates significant growth inhibition in multiple myeloma cells in vitro and in vivo. Blood. 2012 Nov 16;120(21):942. PubMed PMID: WOS:000313838902019; English.
   Web of Science ®Google Scholar
• Ichikawa K, Abe T, Nagase H, et al. TAS-117, a highly selective non-ATP competitive inhibitor of AKT demonstrated antitumor activity in combination with chemotherapeutic agents and molecular targeted drugs. Mol Cancer Ther. 2013 Nov;12(11). DOI:10.1158/1535-7163.Targ-13-C177. PubMed PMID: WOS:000209496800606; English.
   Web of Science ®Google Scholar
• Azaro A, Rodon J, Calles A, et al. A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt inhibitor, in patients with advanced or metastatic cancer. Invest New Drug. 2015 Jun;33(3):710–719. PubMed PMID: WOS:000354621100017; English.
   PubMed Web of Science ®Google Scholar
• Rezai K, Huguet S, Madar O, et al. Abstract 2049: pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. Cancer Res. 2016;76(14 Supplement):2049–2049.
   Google Scholar
• Angevin E, Cassier PA, Italiano A, et al. Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study. Eur J Cancer. 2017 Sep;83:194–202. PubMed PMID: WOS:000408273800023; English.
   PubMed Web of Science ®Google Scholar
• Machl A, Wilker EW, Tian H, et al. M2698 is a potent dual-inhibitor of p70S6K and Akt that affects tumor growth in mouse models of cancer and crosses the blood-brain barrier. Am J Cancer Res. 2016;6(4):806–818. PubMed PMID: WOS:000375261700007; English.
   PubMed Web of Science ®Google Scholar
• Huck BR, Tian H, Syed S, et al. Evaluation of p70S6K/Akt inhibitor MSC2363318A in patient derived xenograft (PDX) models of breast cancer. Cancer Res. 2014 Oct 1;74(19). DOI:10.1158/1538-7445.Am2014-4516. PubMed PMID: WOS:000349910202489; English.
   PubMed Web of Science ®Google Scholar
• Tsimberidou AM, Verschraegen C, Heestand G, et al. A first in human, dose escalation trial of Msc2363318a-a dual P70s6k/Akt inhibitor, for patients with advanced malignancies. Ann Oncol. 2015 Mar;26:25–25. PubMed PMID: WOS:000354729300026; English.
   Web of Science ®Google Scholar
• McLaughlin J, Markovtsov V, Li H, et al. Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identified through an image-based phenotypic screen. J Cancer Res Clin. 2010 Jan;136(1):99–113. PubMed PMID: WOS:000271981600012; English.
   PubMed Web of Science ®Google Scholar
• Peter B, Herrmann H, Gleixner KV, et al. The aurora-kinase inhibitor R763/AS703569 exerts major growth-inhibitory and apoptosis-inducing effects on neoplastic mast cells. Blood. 2010 Nov 19;116(21):1620–1620. PubMed PMID: WOS:000289662204392; English.
   Web of Science ®Google Scholar
• Sonet A, Graux C, Maertens J, et al. Phase I, dose-escalation study of 2 dosing regimens of AS703569, an inhibitor of aurora and other kinases, administered orally in patients with advanced hematological malignancies. Blood. 2008;112(11):2963–2963.
   Web of Science ®Google Scholar
• Renshaw JS, Patnaik A, Gordon M, et al. A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results. J Clin Oncol. 2007 Jun 20;25(18_suppl):14130–14130. DOI:10.1200/jco.2007.25.18_suppl.14130.
   Web of Science ®Google Scholar
• Awada A, Alexandre J, Gianella-Borradori A, et al. Phase I and pharmacokinetic (PK) study of two regimens combining the aurora kinase inhibitor AS703569 and gemcitabine in patients with advanced solid tumors. Cancer Res. 2010 Apr;70. DOI:10.1158/1538-7445.Am10-2754. PubMed PMID: WOS:000209823904229; English.
   Web of Science ®Google Scholar
• Testa JR, Tsichlis PN. AKT signaling in normal and malignant cells. Oncogene. 2005 Nov 14;24(50):7391–7393. PubMed PMID: WOS:000233201900001; English.
   PubMed Web of Science ®Google Scholar
• She QB, Chandarlapaty S, Ye Q, et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. Plos One. 2008 Aug 26;3(8). DOI:10.1371/journal.pone.0003065. PubMed PMID: WOS:000264796300011; English.
   PubMed Web of Science ®Google Scholar
• Yi KH, Lauring J. Recurrent AKT mutations in human cancers: functional consequences and effects on drug sensitivity. Oncotarget. 2016 Jan 26;7(4):4241–4251. PubMed PMID: 26701849; PubMed Central PMCID: PMCPMC4826202.
   PubMedGoogle Scholar