Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine

References

• Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501. doi:10.1038/nature12912
   PubMed Web of Science ®Google Scholar
• Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273–291. doi:10.1038/nrclinonc.2018.28
   PubMed Web of Science ®Google Scholar
• Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 2002;1(9):707–717. doi:10.1158/1535-7163.MCT-11-0712
   PubMed Web of Science ®Google Scholar
• Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016;82(4):943–956. doi:10.1111/bcp.13021
   PubMed Web of Science ®Google Scholar
• Hinz N, Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Communication and Signaling. 2019;17(1):1–29. doi:10.1186/s12964-019-0450-3
   PubMed Web of Science ®Google Scholar
• Lazaro G, Kostaras E, Vivanco I. Inhibitors in AKTion: ATP-competitive vs allosteric. Biochem Soc Trans. 2020;48(3):933–943. doi:10.1042/BST20190777
   PubMed Web of Science ®Google Scholar
• Smyth LM, Tamura K, Oliveira M, et al. Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1 E17K -mutant, ER-positive metastatic breast cancer. Clin Cancer Res. 2020;26(15):3947–3957. doi:10.1158/1078-0432.CCR-19-3953
   PubMed Web of Science ®Google Scholar
• Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005. doi:10.1016/S0065-230X(05)94002-5
   Web of Science ®Google Scholar
• Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501. doi:10.1038/nrc839
   PubMed Web of Science ®Google Scholar
• Duronio V. The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J. 2008;415:333–344. doi:10.1042/BJ20081056
   PubMed Web of Science ®Google Scholar
• Matheny RW, Adamo ML. Current perspectives on akt akt-ivation and akt-ions. Exp Biol Med. 2009;234(11):1264–1270. doi:10.3181/0904-MR-138
   Web of Science ®Google Scholar
• Gonzalez E, McGraw TE. The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle. 2009;8(16):2502–2508. doi:10.4161/cc.8.16.9335
   PubMed Web of Science ®Google Scholar
• Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169:381–405.
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–1101. doi:10.1126/science.1106148
   PubMed Web of Science ®Google Scholar
• 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;279(39):41189–41196. doi:10.1074/jbc.M406731200
   PubMed Web of Science ®Google Scholar
• A Altomare D, R Khaled A. Homeostasis and the Importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem. 2012;19(22):3748–3762. doi:10.2174/092986712801661130
   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;127(1):125–137. doi:10.1016/j.cell.2006.08.033
   PubMed Web of Science ®Google Scholar
• Li XJ, Leem S-H, Park MH, Kim SM. Regulation of YAP through an Akt-dependent process by 3, 3′-diindolylmethane in human colon cancer cells. Int J Oncol. 2013;43(6):1992–1998. doi:10.3892/ijo.2013.2121
   PubMed Web of Science ®Google Scholar
• Xu Q, Liu L-Z, Qian X, et al. MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res. 2012;40(2):761–774. doi:10.1093/nar/gkr730
   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;19(1):16–23. doi:10.1016/j.tcb.2008.10.003
   PubMed Web of Science ®Google Scholar
• Miller TW, Pérez-Torres M, Narasanna A, 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 breast cancer. Cancer Res. 2009;69(10):4192–4201. doi:10.1158/0008-5472.CAN-09-0042
   PubMed Web of Science ®Google Scholar
• Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565. doi:10.1001/jamaoncol.2016.0891
   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;91(2):231–241. doi:10.1016/S0092-8674(00)80405-5
   PubMed Web of Science ®Google Scholar
• Sangawa A, Shintani M, Yamao N, Kamoshida S. Phosphorylation status of Akt and caspase-9 in gastric and colorectal carcinomas. Int J Clin Exp Pathol. 2014;7(6):3312.
   PubMed Web of Science ®Google Scholar
• Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta Mol Cell Res. 2011;1813(11):1978–1986. doi:10.1016/j.bbamcr.2011.03.010
   PubMed Web of Science ®Google Scholar
• Ogawara Y, Kishishita S, Obata T, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843–21850. doi:10.1074/jbc.M109745200
   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 Biol Chem. 2012;287(14):11151–11163. doi:10.1074/jbc.M111.333922
   PubMed Web of Science ®Google Scholar
• Brown JS, Banerji U. Maximising the potential of AKT inhibitors as anti-cancer treatments. Pharmacol Ther. 2017;172:101–115. doi:10.1016/j.pharmthera.2016.12.001
   PubMed Web of Science ®Google Scholar
• Bertucci F, Ng CKY, Patsouris A, et al. Genomic characterization of metastatic breast cancers. Nature. 2019;569(7757):560–564. doi:10.1038/s41586-019-1056-z
   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;448(7152):439–444. doi:10.1038/nature05933
   PubMed Web of Science ®Google Scholar
• Pascual J, Turner NC. Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann Oncol. 2019;30(7):1051–1060. doi:10.1093/annonc/mdz133
   PubMed Web of Science ®Google Scholar
• Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127. doi:10.1016/j.ccr.2004.06.022
   PubMed Web of Science ®Google Scholar
• Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–404. doi:10.1158/2159-8290.CD-12-0095
   PubMed Web of Science ®Google Scholar
• Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269). doi:10.1126/scisignal.2004088
   Web of Science ®Google Scholar
• Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–7464. doi:10.1038/sj.onc.1209085
   PubMed Web of Science ®Google Scholar
• Robertson JFR, Coleman RE, Cheung K-L, et al. Proliferation and AKT activity biomarker analyses after capivasertib (AZD5363) treatment of patients with ER + invasive breast cancer (STAKT). Clin Cancer Res. 2020;26(7):1574–1585. doi:10.1158/1078-0432.CCR-19-3053
   PubMed Web of Science ®Google Scholar
• Kalinsky K, Hong F, Ck M, et al. AZD5363 in Patients (Pts) with tumors with AKT mutations: NCI-MATCH subprotocol EAY131-Y, A trial of the ECOG-ACRIN Cancer Research Group (EAY131-Y). Eur J Cancer. 2018.
   Google Scholar
• Wolf DM, Yau C, Wulfkuhle J, et al. Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial. NPJ Breast Cancer. 2020;6(1). doi:10.1038/s41523-020-00189-2
   Web of Science ®Google Scholar
• Kim S-B, Dent R, Im S-A, 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;18(10):1360–1372. doi:10.1016/S1470-2045(17)30450-3
   PubMed Web of Science ®Google Scholar
• Schmid P, Abraham J, Chan S, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38(5):423–433. doi:10.1200/JCO.19.00368
   PubMed Web of Science ®Google Scholar
• Dent R, Oliveira M, Isakoff SJ, et al. 139O final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31:S64–S65. doi:10.1016/j.annonc.2020.03.240
   Web of Science ®Google Scholar
• Ma CX, Sanchez C, Gao F, 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(11):2650–2658. doi:10.1158/1078-0432.CCR-15-2160
   PubMed Web of Science ®Google Scholar
• Turner NC, Alarcón E, Armstrong AC, et al. BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA. Ann Oncol. 2019;30(5):774–780. doi:10.1093/annonc/mdz086
   PubMed Web of Science ®Google Scholar
• Jones RH, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020;21(3):345–357. doi:10.1016/S1470-2045(19)30817-4
   PubMed Web of Science ®Google Scholar
• Yap TA, Garrett MD, Walton MI, et al. Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol. 2008;8(4):393–412. doi:10.1016/j.coph.2008.08.004
   Web of Science ®Google Scholar
• Falchook GS, Kurzrock R, Hm A, et al. First-in-man phase i trial of the selective MET inhibitor tepotinib in patients with advanced solid tumors. Clin Cancer Res. 2020;26(6):1237–1246. doi:10.1158/1078-0432.CCR-19-2860
   PubMed Web of Science ®Google Scholar
• Harb W, Saleh MN, Papadopoulos KP, et al. Clinical trial results from the subgroup of lymphoma/CLL in a Phase 1 Study of ARQ 092, a novel pan AKT-inhibitor. Blood. 2015;126(23):5116. doi:10.1182/blood.V126.23.5116.5116
   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. doi:10.1158/1538-7445.am2018-ct024
   Web of Science ®Google Scholar
• Yap TA, Yan L, Patnaik A, et al. Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clin Cancer Res. 2014;20(22):5672–5685. doi:10.1158/1078-0432.CCR-14-0868
   Web of Science ®Google Scholar
• Banerji U, Dean EJ, Pérez-Fidalgo JA, et al. A Phase I Open-Label Study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA -mutated breast and gynecologic cancers. Clin Cancer Res. 2018;24(9):2050–2059. doi:10.1158/1078-0432.CCR-17-2260
   PubMed Web of Science ®Google Scholar
• Ahn DH, Li J, Wei L, et al. Results of an abbreviated phase-II study with the Akt inhibitor MK-2206 in patients with advanced biliary cancer. Sci Rep. 2015;5(1). doi:10.1038/srep12122
   Web of Science ®Google Scholar
• Ramanathan RK, McDonough SL, Kennecke HF, 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(13):2193–2197. doi:10.1002/cncr.29363
   PubMed Web of Science ®Google Scholar
• Dasari A, Overman MJ, Fogelman DR, et al. A phase II and co-clinical study of an AKT inhibitor in patients (pts) with biomarker-enriched, previously treated metastatic colorectal cancer (mCRC). J Clin Oncol. 2016;34(15_suppl):3563. doi:10.1200/JCO.2016.34.15_suppl.3563
   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;21(1). doi:10.1186/s13058-019-1154-8
   Web of Science ®Google Scholar
• Lu W, Defeo-Jones D, Davis L, et al. Abstract #3714: in vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor. Cancer Res. 2009;69:3714.
   Google Scholar
• Yap TA, Yan L, Patnaik A, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29(35):4688–4695. doi:10.1200/JCO.2011.35.5263
   PubMed Web of Science ®Google Scholar
• Tolcher A, Harb W, Sachdev J, et al. 338 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;51:S66. doi:10.1016/s0959-8049(16)30201-5
   Web of Science ®Google Scholar
• Shapiro GI, LoRusso P, Cho DC, et al. A phase Ib open-label dose escalation study of the safety, pharmacokinetics, and pharmacodynamics of cobimetinib (GDC-0973) and ipatasertib (GDC-0068) in patients with locally advanced or metastatic solid tumors. Invest New Drugs. 2021;39(1):163–174. doi:10.1007/s10637-020-00975-6
   PubMed Web of Science ®Google Scholar
• Burris HA, Siu LL, Infante JR, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of the oral AKT inhibitor GSK2141795 (GSK795) in a phase I first-in-human study. J Clin Oncol. 2011;29(15_suppl):3003. doi:10.1200/jco.2011.29.15_suppl.3003
   Web of Science ®Google Scholar
• Saura C, Roda D, Roselló 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;7(1):102–113. doi:10.1158/2159-8290.CD-16-0512
   PubMed Web of Science ®Google Scholar
• Smyth LM, Batist G, Meric-Bernstam F, et al. Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer. NPJ Breast Cancer. 2021;7(1). doi:10.1038/s41523-021-00251-7
   Web of Science ®Google Scholar
• Kalinsky K, Hong F, McCourt CK, et al. Effect of capivasertib in patients with an AKT1 E17K -mutated tumor. JAMA Oncol. 2021;7(2):271. doi:10.1001/jamaoncol.2020.6741
   Web of Science ®Google Scholar
• Bleeker FE, Felicioni L, Buttitta F, et al. AKT1E17K in human solid tumours. Oncogene. 2008;27(42):5648–5650. doi:10.1038/onc.2008.170
   PubMed Web of Science ®Google Scholar
• Kehr EL, Jorns JM, Ang D, et al. Mucinous breast carcinomas lack PIK3CA and AKT1 mutations. Hum Pathol. 2012;43(12):2207–2212. doi:10.1016/j.humpath.2012.03.012
   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;35(20):2251–2259. doi:10.1200/JCO.2017.73.0143
   PubMed Web of Science ®Google Scholar
• Bose S, Kalinsky K. Durable clinical activity to the AKT inhibitor ipatasertib in a heavily pretreated patient with an AKT1 E17K mutant metastatic breast cancer. Clin Breast Cancer. 2021;21(3):e150–e153. doi:10.1016/j.clbc.2020.10.002
   Web of Science ®Google Scholar
• Flaherty KT, Gray RJ, Chen AP, et al. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: national cancer institute molecular analysis for therapy choice (NCI-MATCH). J Clin Oncol. 2020;38(33):3883–3894. doi:10.1200/JCO.19.03010
   PubMed Web of Science ®Google Scholar
• Jette N, Lees-Miller SP. The DNA-dependent protein kinase: a multifunctional protein kinase with roles in DNA double strand break repair and mitosis. Prog Biophys Mol Biol. 2015;117(2–3):194–205. doi:10.1016/j.pbiomolbio.2014.12.003
   PubMed Web of Science ®Google Scholar
• Bozulic L, Surucu B, Hynx D, Hemmings BA. PKBα/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell. 2008;30(2):203–213. doi:10.1016/j.molcel.2008.02.024
   PubMed Web of Science ®Google Scholar
• Wendel H-G, Stanchina ED, Fridman JS, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature. 2004;428(6980):332–337. doi:10.1038/nature02369
   PubMed Web of Science ®Google Scholar
• Hirai H, Sootome H, Nakatsuru Y, 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(7):1956–1967. doi:10.1158/1535-7163.MCT-09-1012
   PubMed Web of Science ®Google Scholar
• VanderWeele DJ, Zhou R, Rudin CM. Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther. 2004;3(12):1605–1613.
   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;11(4):873–887. doi:10.1158/1535-7163.MCT-11-0824-T
   PubMed 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;36(15_suppl):1007. doi:10.1200/jco.2018.36.15_suppl.1007
   PubMed Web of Science ®Google Scholar
• Dent R, Kim SB, Oliveira M, et al. Abstract GS3-04: double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple. Cancer Res. 2021;81:GS3-04 LP-GS3-04.
   Web of Science ®Google Scholar
• Crabb SJ, Birtle AJ, Martin K, et al. ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer. Invest New Drugs. 2017;35(5):599–607. doi:10.1007/s10637-017-0433-4
   Web of Science ®Google Scholar
• Crabb SJ, Griffiths G, Marwood E, et al. Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (procaid). J Clin Oncol. 2021;39(3):190–201. doi:10.1200/JCO.20.01576
   PubMed Web of Science ®Google Scholar
• Yap TA, Omlin A, De Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592–1605. doi:10.1200/JCO.2011.37.6418
   PubMed Web of Science ®Google Scholar
• Wang L-E, Ma H, Hale KS, et al. Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes. J Cancer Res Clin Oncol. 2012;138(3):377–385. doi:10.1007/s00432-011-1103-0
   PubMed Web of Science ®Google Scholar
• Westin SN, Sill M, Coleman RL, et al. Limited access safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2016;141:4–5. doi:10.1016/j.ygyno.2016.04.038
   Google Scholar
• Tolcher AW, Kurzrock R, Valero V, et al. Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors. Cancer Chemother Pharmacol. 2020;85(4):673–683. doi:10.1007/s00280-020-04038-8
   Web of Science ®Google Scholar
• Algazi AP, Muthukumar AH, O’Brien K, et al. Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma. J Clin Oncol. 2015;33(15_suppl):9068. doi:10.1200/jco.2015.33.15_suppl.9068
   Web of Science ®Google Scholar
• Shoushtari AN, Kudchadkar RR, Panageas K, et al. A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced uveal melanoma. J Clin Oncol. 2016;34(15_suppl):9511. doi:10.1200/JCO.2016.34.15_suppl.9511
   Web of Science ®Google Scholar
• Irvine M, Stewart A, Pedersen B, et al. Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma. Oncogenesis. 2018;7(9):72. doi:10.1038/s41389-018-0081-3
   Web of Science ®Google Scholar
• Algazi AP, Moon J, Chmielowski B, et al. SWOG S1221: a phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173). J Clin Oncol. 2017;35(15_suppl):2578. doi:10.1200/JCO.2017.35.15_suppl.2578
   Web of Science ®Google Scholar
• Ramaswamy B, Mrozek E, Lustberg M, et al. Abstract LB-216: NCI 9455: phase II study of trametinib followed by trametinib plus AKT inhibitor, GSK2141795 in patients with advanced triple negative breast cancer. Cancer Res. 2016;76:LB-216-LB-216.
   Web of Science ®Google Scholar
• Liu JF, Gray KP, Wright AA, et al. Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer. Gynecol Oncol. 2019;154(1):95–101. doi:10.1016/j.ygyno.2019.05.003
   PubMed Web of Science ®Google Scholar
• Bokobza SM, Jiang Y, Weber AM, Devery AM, Ryan AJ. Combining AKT inhibition with chloroquine and gefitinib prevents compensatory autophagy and induces cell death in EGFR mutated NSCLC cells. Oncotarget. 2014;5(13):4765–4778. doi:10.18632/oncotarget.2017
   Google Scholar
• Li H, Schmid-Bindert G, Wang D, et al. Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome gefitinib-resistance in non-small cell lung cancer cell lines. Adv Med Sci. 2011;56(2):275–284. doi:10.2478/v10039-011-0043-x
   PubMed Web of Science ®Google Scholar
• Lin -C-C, Yu C-J, Ho -C-C, et al. P1.12 - a Phase I Dose Defining Study for MK-2206 combined with gefitinib in NSCLC population enriched with EGFR mutation. Ann Oncol. 2015;26:ii16. doi:10.1093/annonc/mdv090.12
   Google Scholar
• Wisinski KB, Tevaarwerk AJ, Burkard ME, 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. Clin Cancer Res. 2016;22(11):2659–2667. doi:10.1158/1078-0432.CCR-15-2365
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Khan K, Ong M, et al. Antitumor activity in RAS -driven tumors by blocking AKT and MEK. Clin Cancer Res. 2015;21(4):739–748. doi:10.1158/1078-0432.CCR-14-1901
   PubMed Web of Science ®Google Scholar
• Do K, Speranza G, Bishop R, 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(3):720–728. doi:10.1007/s10637-015-0212-z
   PubMed Web of Science ®Google Scholar
• Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3(4):516–522. doi:10.1001/jamaoncol.2016.5383
   PubMed Web of Science ®Google Scholar
• Costa C, Wang Y, Ly A, et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov. 2020;10(1):72–85. doi:10.1158/2159-8290.CD-18-0830
   PubMed Web of Science ®Google Scholar
• Wander SA, Juric D, Supko JG, et al. Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTI. J Clin Oncol. 2020;38(15_suppl):1066. doi:10.1200/JCO.2020.38.15_suppl.1066
   Google Scholar
• Oliveira M, Villagrasa P, Ciruelos E, et al. Abstract OT-35-01: solti-1507 A phase ib study of ipatasertib and anti-her2 therapy in her2-positive advanced breast cancer with pik3ca mutation (ipather). Cancer Res. 2021;81:OT-35-01-OT-35-01.
   Google Scholar
• Ibrahim YH, García-García C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2(11):1036–1047. doi:10.1158/2159-8290.CD-11-0348
   PubMed Web of Science ®Google Scholar
• Rehman FL, Lord CJ, Ashworth A. The promise of combining inhibition of PI3K and PARP as cancer therapy. Cancer Discov. 2012;2(11):982–984. doi:10.1158/2159-8290.CD-12-0433
   Web of Science ®Google Scholar
• Yap TA, Kristeleit R, Michalarea V, et al. Phase I trial of the PARP inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2 - and Non– BRCA1/2 -mutant cancers. Cancer Discov. 2020;10(10):1528–1543. doi:10.1158/2159-8290.CD-20-0163
   PubMed Web of Science ®Google Scholar
• Ma CX, Crowder RJ, Ellis MJ. Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors. Steroids. 2011;76(8):750–752. doi:10.1016/j.steroids.2011.02.023
   Web of Science ®Google Scholar
• Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261–275. doi:10.1038/nrc3920
   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;23:6823–6832.
   PubMed Web of Science ®Google Scholar
• Ferrari AC, Chen Y-H, Hudes GR, et al. E2809: androgen receptor (AR) modulation by bicalutamide (Bic) and MK-2206 (MK) in men with rising PSA at high-risk of progression after local prostate cancer (PC) treatment.. J Clin Oncol. 2016;34(2_suppl):9. doi:10.1200/jco.2016.34.2_suppl.9
   Web of Science ®Google Scholar
• Kolinsky MP, Rescigno P, Bianchini D, et al. A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2020;31:619–625. doi:10.1016/j.annonc.2020.01.074
   PubMed Web of Science ®Google Scholar
• Shore ND, Mellado B, Shah S, et al. A phase I study of capivasertib in combination with Abiraterone acetate in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2021;39:85. doi:10.1200/JCO.2021.39.6_suppl.85
   Web of Science ®Google Scholar
• De Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized phase II study evaluating AKT blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928–936. doi:10.1158/1078-0432.CCR-18-0981
   PubMed Web of Science ®Google Scholar
• de Bono JS, Bracarda S, Sternberg CN, et al. LBA4 IPATential150: phase III study of ipatasertib (ipat) plus Abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2020;31:S1153–S1154. doi:10.1016/j.annonc.2020.08.2250
   Web of Science ®Google Scholar
• Zhang Y, Yan H, Xu Z, et al. Molecular basis for class side effects associated with PI3K/AKT/mTOR pathway inhibitors. Expert Opin Drug Metab Toxicol. 2019;15(9):767–774. doi:10.1080/17425255.2019.1663169
   PubMed Web of Science ®Google Scholar
• Chien AJ, Cockerill A, Fancourt C, 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 Res Treat. 2016;155(3):521–530. doi:10.1007/s10549-016-3701-7
   PubMed Web of Science ®Google Scholar
• Chien AJ, Tripathy D, Albain KS, et al. MK-2206 and standard neoadjuvant chemotherapy improves response in patients with human epidermal growth factor receptor 2–positive and/or hormone receptor–negative breast cancers in the I-SPY 2 trial. J Clin Oncol. 2020. doi:10.1200/JCO.19.01027
   Web of Science ®Google Scholar
• Weisner J, Landel I, Reintjes C, et al. Preclinical efficacy of covalent-allosteric AKT inhibitor borussertib in combination with trametinib in KRAS-mutant pancreatic and colorectal cancer. Cancer Res. 2019:canres.2861.2018. doi:10.1158/0008-5472.CAN-18-2861
   Web of Science ®Google Scholar
• Lang L, Shay C, Zhao X, et al. Simultaneously inactivating Src and AKT by saracatinib/capivasertib co-delivery nanoparticles to improve the efficacy of anti-Src therapy in head and neck squamous cell carcinoma. J Hematol Oncol. 2019;12(1). doi:10.1186/s13045-019-0827-1
   Web of Science ®Google Scholar
• Bendell, J. C. 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;30:LBA3501–LBA3501.
   Google Scholar
• Blagden, S. P. et al. Phase IB dose escalation and expansion study of akt inhibitor afuresertib with carboplatin and paclitaxel in recurrent platinum-resistant ovarian cancer. Clin Cancer Res. 2019. doi:10.1158/1078-0432.CCR-18-2277
   Web of Science ®Google Scholar
• Lakhani, N. 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. doi:10.1200/jco.2017.35.15_suppl.2524.
   Web of Science ®Google Scholar
• Tolcher, A. W. 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;75:183–189.
   Google Scholar
• Westin, S.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;8:v130–v131.
   Google Scholar
• LaraJr., P. N.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;21:4321–4326.
   Google Scholar