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

Mundi, Prabhjot S.; Sachdev, Jasgit; McCourt, Carolyn; Kalinsky, Kevin

doi:10.1111/bcp.13021

Cited by 272PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerCancer Mechanisms and Therapy

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

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Mundi, Prabhjot S., Sachdev, Jasgit, McCourt, Carolyn, Kalinsky, Kevin·2016·British Journal of Clinical Pharmacology

DOI 10.1111/bcp.13021PMC PMC5137819

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Abstract

The phosphatidylinositol‐3 kinase (PI3K)–AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K–AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well‐characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.

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At the molecular level, IL-6 increases the activity of DNMT1 with activating effects on JAK/STAT3, NF-κB and PI3K/AKT/mTOR signaling pathways, affecting regulation of autophagy-related functions required to maintain cellular homeostasis under stress such as a prenatal insult.
“At the molecular level, IL-6 increases the activity of DNA methyltransferases 1 (DNMT1) with activating effects on the JAK/STAT3, NF-κB and PI3K/AKT/mTOR signaling pathways [144–148] affecting the regulation of autophagy-related functions, that are required to maintain cellular homeostasis under stress [149], such as a prenatal insult.”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [148]

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PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
Evaluation of Factors Related to Late Recurrence - Later than 10 Years after the Initial Treatment - in Primary Breast Cancer
Nishimura, R., Osako, T., Nishiyama, Y., Tashima, R., Nakano, M., Fujisue, M., Toyozumi, Y., & Arima, N. (2013) · Oncology · doi:10.1159/000353099 · Cited by 13,239 · see citing works
Comprehensive molecular portraits of human breast tumours
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11412 · Cited by 12,129 · see citing works
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · see citing works
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115 · see citing works
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,041 · see citing works
Integrated genomic characterization of endometrial carcinoma
The Cancer Genome Atlas Research Network, & Levine, D. A. (2013) · Nature · doi:10.1038/nature12113 · Cited by 5,784 · see citing works
Mutational landscape and significance across 12 major cancer types
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., et al. (2013) · Nature · doi:10.1038/nature12634 · Cited by 4,419 · see citing works
PI3K/Akt signalling pathway and cancer
Vara, J. Á. F., Casado, E., de Castro, J., Cejas, P., Belda-Iniesta, C., & González-Barón, M. (2003) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2003.07.007 · Cited by 2,446 · see citing works
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L. M., Wang, S. I., Zheng, Z., Bose, S., Call, K. M., Tsou, H. C., Peacoke, M., et al. (1997) · Nature Genetics · doi:10.1038/ng0597-64 · Cited by 2,067 · see citing works
Guide to receptors and channels (GRAC), 5th edition
Alexander, S., Mathie, A., & Peters, J. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01649_1.x · Cited by 1,947 · see citing works
Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia
Furman, R. R., Sharman, J. P., Coutre, S. E., Cheson, B. D., Pagel, J. M., Hillmen, P., Barrientos, J. C., Zelenetz, A. D., Kipps, T. J., Flinn, I. W., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1315226 · Cited by 1,711 · see citing works
The landscape of cancer genes and mutational processes in breast cancer
Stephens, P. J., Tarpey, P. S., Davies, H. R., Loo, P. V., Greenman, C., Wedge, D. C., Nik‐Zainal, S., Martin, S., Varela, I., Bignell, G. R., et al. (2012) · Nature · doi:10.1038/nature11017 · Cited by 1,686 · see citing works
Pten is essential for embryonic development and tumour suppression
Cristofano, A. D., Pesce, B., Cordon‐Cardo, C., & Pandolfi, P. P. (1998) · Nature Genetics · doi:10.1038/1235 · Cited by 1,518 · see citing works
Perturbations of the AKT signaling pathway in human cancer
Altomare, D. A., & Testa, J. R. (2005) · Oncogene · doi:10.1038/sj.onc.1209085 · Cited by 1,326 · see citing works
The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Huang, J., & Manning, B. D. (2008) · Biochemical Journal · doi:10.1042/bj20080281 · Cited by 1,237 · see citing works
A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus
Mayo, L. D., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181181198 · Cited by 1,230 · see citing works
An integrative genomic and proteomic analysis of pik3ca, pten, and akt mutations in breast cancer.
Stemke-Hale, K., Gonzalez-Angulo, A. M., Lluch, A., Neve, R. M., Kuo, W.-L., Davies, M., Carey, M., Hu, Z., Guan, Y., Sahin, A., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6854 · Cited by 1,054 · see citing works
mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways
Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., Manola, J., Brugarolas, J., McDonnell, T. J., Golub, T. R., et al. (2004) · Nature Medicine · doi:10.1038/nm1052 · Cited by 964 · see citing works
CREB Is a Regulatory Target for the Protein Kinase Akt/PKB
Du, K., & Montminy, M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32377 · Cited by 952 · see citing works
MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs In vitro and In vivo
Hirai, H., Sootome, H., Nakatsuru, Y., Miyama, K., Taguchi, S., Tsujioka, K., Ueno, Y., Hatch, H., Majumder, P. K., Pan, B., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-1012 · Cited by 930 · see citing works
Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice
Holland, E. C., Celestino, J., Dai, C., Schaefer, L., Sawaya, R. A., & Fuller, G. N. (2000) · Nature Genetics · doi:10.1038/75596 · Cited by 906 · see citing works
The Regulation and Activities of the Multifunctional Serine/Threonine Kinase Akt/PKB
Kandel, E., & Hay, N. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4690 · Cited by 867 · see citing works
Landscape of genomic alterations in cervical carcinomas
Ojesina, A. I., Lichtenstein, L., Freeman, S. S., Pedamallu, C. S., Imaz-Rosshandler, I., Pugh, T. J., Cherniack, A. D., Ambrogio, L., Cibulskis, K., Bertelsen, B. I., et al. (2013) · Nature · doi:10.1038/nature12881 · Cited by 861 · see citing works
High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice
Suzuki, A., de la Pompa, J. L., Stambolic, V., Elia, A., Sasaki, T., Barrantes, I. D. B., Ho, A., Wakeham, A. C., ltie, A., Khoo, W., et al. (1998) · Current Biology · doi:10.1016/s0960-9822(07)00488-5 · Cited by 819 · see citing works
FoxO transcription factors; Regulation by AKT and 14-3-3 proteins
Tzivion, G., Dobson, M., & Ramakrishnan, G. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.06.002 · Cited by 728 · see citing works
Akt Phosphorylates and Negatively Regulates Apoptosis Signal-Regulating Kinase 1
Kim, A. H., Khursigara, G., Sun, X., Franke, T. F., & Chao, M. V. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.3.893-901.2001 · Cited by 710 · see citing works
Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance
McCubrey, J. A., Steelman, L. S., Abrams, S. L., Lee, J. T., Chang, F., Bertrand, F. E., Navolanic, P. M., Terrian, D. M., Franklin, R. A., D’Assoro, A. B., et al. (2006) · Advances in Enzyme Regulation · doi:10.1016/j.advenzreg.2006.01.004 · Cited by 656 · see citing works
Deregulated Akt3 Activity Promotes Development of Malignant Melanoma
Stahl, J. M., Sharma, A. K., Cheung, M., Zimmerman, M., Cheng, J. Q., Bosenberg, M., KESTER, M. A., Sandirasegarane, L., & Robertson, G. P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1399 · Cited by 595 · see citing works
FOXO transcription factors
Carter, M. E., & Brunet, A. (2007) · Current Biology · doi:10.1016/j.cub.2007.01.008 · Cited by 581 · see citing works
Identification of a PKB/Akt Hydrophobic Motif Ser-473 Kinase as DNA-dependent Protein Kinase
Feng, J., Park, J., Cron, P. D., Heß, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406731200 · Cited by 488 · see citing works
Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background
Davies, B. R., Greenwood, H., Dudley, P., Crafter, C., Yu, D.-H., Zhang, J., Li, J., Gao, B., Ji, Q., Maynard, J., et al. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0824-t · Cited by 480 · see citing works
The Akt kinases: Isoform specificity in metabolism and cancer
Gonzalez, E., & McGraw, T. E. (2009) · Cell Cycle · doi:10.4161/cc.8.16.9335 · Cited by 474 · see citing works
Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis
Gottlieb, T. M., Martínez-Leal, J. F., Seger, R., Taya, Y., & Oren, M. (2002) · Oncogene · doi:10.1038/sj.onc.1205181 · Cited by 473 · see citing works
Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors
Dienstmann, R., Rodon, J. A., Serra, V., & Tabernero, J. M. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0639 · Cited by 464 · see citing works
PTEN, more than the AKT pathway
Blanco‐Aparicio, C., Renner, O., Martínez-Leal, J. F., & Carnero, A. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm052 · Cited by 403 · see citing works
Akt-regulated pathways in prostate cancer
Majumder, P. K., & Sellers, W. R. (2005) · Oncogene · doi:10.1038/sj.onc.1209096 · Cited by 343 · see citing works
Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer.
Malik, S. N., Brattain, M. G., Ghosh, P., Troyer, D. A., Prihoda, T. J., Bedolla, R. G., & Kreisberg, J. I. (2002) · PubMed · Cited by 321 · see citing works
Prognostic Significance of Activated Akt Expression in Melanoma: A Clinicopathologic Study of 292 Cases
Dai, D. L., Martinka, M., & Li, G. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.07.168 · Cited by 318 · see citing works
Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: The MPAKT model
Majumder, P., Yeh, J.-J., George, D., Febbo, P., Kum, J., Xue, Q., Bikoff, R., Ma, H.-K., Kantoff, P., Golub, T., et al. (2003) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1232229100 · Cited by 299 · see citing works
Life with a Single Isoform of Akt: Mice Lacking Akt2 and Akt3 Are Viable but Display Impaired Glucose Homeostasis and Growth Deficiencies
Dummler, B. A., Tschopp, O., Hynx, D., Yang, Z., Dirnhofer, S., & Hemmings, B. A. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00722-06 · Cited by 282 · see citing works
Activation of Akt (Protein Kinase B) in Mammary Epithelium Provides a Critical Cell Survival Signal Required for Tumor Progression
Hutchinson, J. N., Jin, J., Cardiff, R. D., Woodgett, J. R., & Muller, W. J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.6.2203-2212.2001 · Cited by 281 · see citing works
Effects of Deguelin on the Phosphatidylinositol 3-Kinase/Akt Pathway and Apoptosis in Premalignant Human Bronchial Epithelial Cells
Chun, K., Kosmeder, J. W., Sun, S., Pezzuto, J. M., Lotan, R., Hong, W. K., & Lee, H. (2003) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/95.4.291 · Cited by 255 · see citing works
Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma
Davies, M. A., Stemke‐Hale, K., Lin, E., Tellez, C. S., Deng, W., Gopal, Y. N. V., Woodman, S. E., Calderone, T. L., Ju, Z., Lazar, A. J., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1985 · Cited by 250 · see citing works
The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models
Carnero, A., & Paramio, J. M. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00252 · Cited by 231 · see citing works
Akt inhibitors in clinical development for the treatment of cancer
Pal, S. K., Reckamp, K. L., Yu, H., & Figlin, R. A. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.520701 · Cited by 227 · see citing works
Akt3-Mediated Resistance to Apoptosis in B-RAF–Targeted Melanoma Cells
Shao, Y., & Aplin, A. E. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4471 · Cited by 194 · see citing works
The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation
Bedogni, B., Welford, S. M., Cassarino, D. S., Nickoloff, B. J., Giaccia, A. J., & Powell, M. B. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.11.005 · Cited by 178 · see citing works
The Akt pathway in human breast cancer: a tissue-array-based analysis
Bose, S., Chandran, S., Mirocha, J., & Bose, N. (2005) · Modern Pathology · doi:10.1038/modpathol.3800525 · Cited by 177 · see citing works
Mammary epithelial stem cells
Smith, G. H., & Chepko, G. (2001) · Microscopy Research and Technique · doi:10.1002/1097-0029(20010115)52:2 · Cited by 173 · see citing works
Targeting the AKT protein kinase for cancer chemoprevention
Crowell, J. A., Steele, V. E., & Fay, J. R. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0120 · Cited by 170 · see citing works
Mammary gland involution is delayed by activated Akt in transgenic mice
Schwertfeger, K. L., Richert, M. M., & Anderson, S. M. (2001) · Molecular Endocrinology · doi:10.1210/mend.15.6.0663 · Cited by 169 · see citing works
Regulation of Akt signaling activation by ubiquitination
Yang, W.-L., Wu, C.-Y., Wu, J., & Lin, H.-K. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10508 · Cited by 164 · see citing works
Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours
Crul, M., Rosing, H., de Klerk, G. J., et al. (2002) · European Journal of Cancer · doi:10.1016/s0959-8049(02)00127-2 · Cited by 161 · see citing works
The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential.
Ahmed, N. N., Franke, T. F., Bellacosa, A., Datta, K., Gonzalez-Portal, M. E., Taguchi, T., Testa, J. R., & Tsichlis, P. N. (1993) · PubMed · Cited by 160 · see citing works
Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor
Xin, L., Teitell, M. A., Lawson, D. A., Kwon, A., Mellinghoff, I. K., & Witte, O. N. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602567103 · Cited by 160 · see citing works
Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma
Tolcher, A. W., Patnaik, A., Papadopoulos, K. P., Rasco, D. W., Becerra, C. R., Allred, A. J., Orford, K., Aktan, G., Ferron-Brady, G., Ibrahim, N., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-014-2615-5 · Cited by 158 · see citing works
Protein Kinase B/Akt Acts via Glycogen Synthase Kinase 3 To Regulate Recycling of αvβ3 and α5β1 Integrins
Roberts, M. S., Woods, A. J., Dale, T. C., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1505-1515.2004 · Cited by 158 · see citing works
Cross-Talk between NFkB and the PI3-Kinase/AKT Pathway Can Be Targeted in Primary Effusion Lymphoma (PEL) Cell Lines for Efficient Apoptosis
Hussain, A. R., Ahmed, S. O., Ahmed, M., Khan, O. S., Abdulmohsen, S. A., Platanias, L. C., Al-Kuraya, K. S., & Shahab Uddin, M. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039945 · Cited by 154 · see citing works
Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers
Parikh, C., Janakiraman, V., Wu, W., Foo, C. K., Kljavin, N. M., Chaudhuri, S., Stawiski, E. W., Lee, B., Lin, J. M., Li, H., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204384109 · Cited by 146 · see citing works
Protein kinase B: signalling roles and therapeutic targeting
Sale, E. M., & Sale, G. J. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7274-9 · Cited by 142 · see citing works
Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithioI-3-thione (Oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethylnitrosamine and uracil mustard
Wattenberg, L. W., & Bueding, E. (1986) · Carcinogenesis · doi:10.1093/carcin/7.8.1379 · Cited by 142 · see citing works
The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma
Spencer, A., Yoon, S.-S., Harrison, S. J., Morris, S. R., Smith, D. A., Brigandi, R. A., Gauvin, J., Kumar, R., Opalinska, J. B., & Chen, C. (2014) · Blood · doi:10.1182/blood-2014-03-559963 · Cited by 142 · see citing works
Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias
Kim, M. S., Jeong, E. G., Yoo, N. J., & Lee, S. H. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604212 · Cited by 140 · see citing works
Posttranslational regulation of Akt in human cancer
Chan, C., Jo, U., Kohrman, A. Q., Rezaeian, A. H., Chou, P.-C., Logothetis, C. J., & Lin, H. (2014) · Cell & Bioscience · doi:10.1186/2045-3701-4-59 · Cited by 139 · see citing works
The integration of chemotherapy into a combined modality approach for cancer treatment
Carter, S. K., & Comis, R. L. (1975) · Cancer Treatment Reviews · doi:10.1016/s0305-7372(75)80003-x · Cited by 134 · see citing works
Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer
Do, K. T., Speranza, G., Bishop, R. J., Khin, S. A., Rubinstein, L., Kinders, R. J., Datiles, M. B., Eugeni, M. A., Lam, M. H., Doyle, L. A., et al. (2015) · Investigational New Drugs · doi:10.1007/s10637-015-0212-z · Cited by 133 · see citing works
Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma
Ni, D., Ma, X., Li, H., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1687 · Cited by 132 · see citing works
Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I/II Trial
Richardson, P. G. G., Wolf, J., Jakubowiak, A. J., Zonder, J., Lonial, S., Irwin, D. H., Densmore, J. J., Krishnan, A. Y., Raje, N. S., Bar, M. H., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.9788 · Cited by 121 · see citing works
Tobacco Carcinogen-Induced Cellular Transformation Increases Activation of the Phosphatidylinositol 3′-Kinase/Akt Pathwayin Vitroandin Vivo
West, K. A., Linnoila, I. R., Belinsky, S. A., Harris, C. C., & Dennis, P. A. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3241 · Cited by 120 · see citing works
AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K
Askham, J. M., Platt, F. M., Chambers, P. A., et al. (2009) · Oncogene · doi:10.1038/onc.2009.315 · Cited by 109 · see citing works
Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models
Toren, P., Kim, S., Cordonnier, T., et al. (2014) · European Urology · doi:10.1016/j.eururo.2014.08.006 · Cited by 109 · see citing works
Randomized Placebo-Controlled Phase II Trial of Perifosine Plus Capecitabine As Second- or Third-Line Therapy in Patients With Metastatic Colorectal Cancer
Bendell, J. C., Nemunaitis, J. J., Vukelja, S. J., Hagenstad, C. T., Campos, L. T., Hermann, R. C., Sportelli, P., Gardner, L. R., & Richards, D. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.1980 · Cited by 109 · see citing works
A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors
Hudis, C. A., Swanton, C., Janjigian, Y. Y., Lee, R., Sutherland, S., Lehman, R. J., Chandarlapaty, S., Hamilton, N., Gajria, D., Knowles, J., et al. (2013) · Breast Cancer Research · doi:10.1186/bcr3577 · Cited by 106 · see citing works
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
Gupta, A., Lee, J. H., Wilke, W. W., et al. (2009) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2009.03.004 · Cited by 105 · see citing works
Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set
Park, E. S., Rabinovsky, R., Carey, M. S., Hennessy, B. T., Agarwal, R., Liu, W., Ju, Z., Deng, W., Lu, Y., Woo, H. G., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0743 · Cited by 102 · see citing works
Molecular determinants of Akt-induced keratinocyte transformation
Segrelles, C., Moral, M., Lara, M. F., Ruiz, S., Santos, M., Leis, H., García‐Escudero, R., Martínez‐Cruz, A. B., Martínez‐Palacio, J., Hernández, P., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209155 · Cited by 102 · see citing works
Molecular Mechanism of an Oncogenic Mutation That Alters Membrane Targeting: Glu17Lys Modifies the PIP Lipid Specificity of the AKT1 PH Domain
Landgraf, K. E., Pilling, C., & Falke, J. J. (2008) · Biochemistry · doi:10.1021/bi801683k · Cited by 99 · see citing works
Delayed mammary gland involution in MMTV-AKT1 transgenic mice
Ackler, S., Ahmad, S., Tobias, C. A., Johnson, M. D., & Glazer, R. I. (2002) · Oncogene · doi:10.1038/sj.onc.1205052 · Cited by 95 · see citing works
Deregulated Activity of Akt in Epithelial Basal Cells Induces Spontaneous Tumors and Heightened Sensitivity to Skin Carcinogenesis
Segrelles, C., Lu, J., Hammann, B. D., Santos, M., Moral, M., Cascallana, J. L., Lara, M. F., Rho, O., Carbajal, S., Traag, J., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2564 · Cited by 94 · see citing works
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 ( S 1005)
Ramanathan, R. K., McDonough, S. L., Kennecke, H. F., Iqbal, S., Baranda, J. C., Seery, T. E., Lim, H. J., Hezel, A. F., Vaccaro, G. M., & Blanke, C. D. (2015) · Cancer · doi:10.1002/cncr.29363 · Cited by 91 · see citing works
Targeting PI 3‐kinase ( PI 3 K ), AKT and m TOR axis in lymphoma
Blachly, J. S., & Baiocchi, R. A. (2014) · British Journal of Haematology · doi:10.1111/bjh.13065 · Cited by 91 · see citing works
Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma
Oki, Y., Fanale, M. A., Romaguera, J. E., Fayad, L., Fowler, N. H., Copeland, A. R. M., Samaniego, F., Kwak, L. W., Neelapu, S. S., Wang, M. L., et al. (2015) · British Journal of Haematology · doi:10.1111/bjh.13603 · Cited by 88 · see citing works
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
Lara, P. N., Longmate, J., Mack, P. C., Kelly, K. L., Socinski, M. A., Salgia, R., Gitlitz, B. J., Li, T., Koczywas, M., Reckamp, K. L., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3281 · Cited by 85 · see citing works
Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes
Boyault, S., Drouet, Y., Navarro, C., Bachelot, T., Lasset, C., Treilleux, I., Tabone, É., Puisieux, A., & Wang, Q. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-011-1518-y · Cited by 80 · see citing works
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
Ma, C. X., Sanchez, C. G., Gao, F., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2160 · Cited by 77 · see citing works
Recent Progress in the Development of ATP-Competitive and Allosteric Akt Kinase Inhibitors
Lindsley, C. W., Stanley, B., Melissa, Y., et al. (2007) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607781696864 · Cited by 72 · see citing works
A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST)
Tolcher, A. W., Yap, T. A., Fearen, I., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.3503 · Cited by 63 · see citing works
Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study
Jakubowiak, A. J., Richardson, P. G. G., Zimmerman, T. M., Alsina, M., Kaufman, J. L., Kandarpa, M., Kraftson, S. J., Ross, C. W., Harvey, C., Hideshima, T., et al. (2012) · British Journal of Haematology · doi:10.1111/j.1365-2141.2012.09173.x · Cited by 62 · see citing works
Cancer Associated E17K Mutation Causes Rapid Conformational Drift in AKT1 Pleckstrin Homology (PH) Domain
Kumar, A., & Purohit, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064364 · Cited by 62 · see citing works
Akt Activation Synergizes with Trp53 Loss in Oral Epithelium to Produce a Novel Mouse Model for Head and Neck Squamous Cell Carcinoma
Moral, M., Segrelles, C., Lara, M. F., Martínez‐Cruz, A. B., Lorz, C., Santos, M., García‐Escudero, R., Lu, J., Kiguchi, K., Buitrago, A., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3240 · Cited by 55 · see citing works
Knockout mouse models and mammary tumorigenesis
Deng, C., & Brodie, S. G. (2001) · Seminars in Cancer Biology · doi:10.1006/scbi.2001.0394 · Cited by 50 · see citing works
Functional analysis of non-hotspot AKT1 mutants found in human breast cancers identifies novel driver mutations: implications for personalized medicine
Yi, K. H., Axtmayer, J., Gustin, J. P., Rajpurohit, A., & Lauring, J. D. (2012) · Oncotarget · doi:10.18632/oncotarget.755 · Cited by 45 · see citing works
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).
Bendell, J. C., Ervin, T. J., Senzer, N. N., Richards, D., Firdaus, I., Lockhart, A. C., Cohn, A. L., Saleh, M. N., Gardner, L. R., Sportelli, P., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.30.15_suppl.lba3501 · Cited by 44 · see citing works
AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2+ breast tumor cells from Balb-neuT mice
Grabinski, N., Möllmann, K., Milde‐Langosch, K., Müller, V., Schumacher, U., Brandt, B., Pantel, K., & Jücker, M. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.01.018 · Cited by 41 · see citing works
Akt Phosphorylation of Deleted in Liver Cancer 1 Abrogates Its Suppression of Liver Cancer Tumorigenesis and Metastasis
Ko, F. C. F., Chan, L., Tung, E. K., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.06.051 · Cited by 40 · see citing works
Buparlisib, an oral pan-PI3K inhibitor for the treatment of breast cancer
Geuna, E., Milani, A., Martinello, R., Aversa, C., Valabrega, G., Scaltriti, M., & Montemurro, F. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.1008132 · Cited by 38 · see citing works
Liraglutide Exerts Antidiabetic Effect via PTP1B and PI3K/Akt2 Signaling Pathway in Skeletal Muscle of KKAy Mice
Ji, W., Chen, X., Lv, J., Wang, M., Ren, S., Yuan, B., Wang, B., & Chen, L. (2014) · International Journal of Endocrinology · doi:10.1155/2014/312452 · Cited by 36 · see citing works
Exploring the Gain of Function Contribution of AKT to Mammary Tumorigenesis in Mouse Models
Blanco‐Aparicio, C., Cañamero, M., Cecilia, Y., Pequeño, B., Renner, O., Ferrer, I., & Carnero, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009305 · Cited by 32 · see citing works
Inhibiting PI3K as a therapeutic strategy against cancer
Paz-Ares, L. G., Blanco‐Aparicio, C., García‐Carbonero, R., & Carnero, A. (2009) · Clinical & Translational Oncology · doi:10.1007/s12094-009-0407-x · Cited by 31 · see citing works
Recent Progress in Mouse Models for Tumor Suppressor Genes and its Implications in Human Cancer
Inoue, K., Fry, E. A., & Taneja, P. (2013) · Clinical Medicine Insights Oncology · doi:10.4137/cmo.s10358 · Cited by 30 · see citing works
Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial
Kalinsky, K. M., Sparano, J. A., Zhong, X., et al. (2018) · Clinical & Translational Oncology · doi:10.1007/s12094-018-1888-2 · Cited by 29 · see citing works
Self-citation
Expression of P-Akt, NFkappaB and their correlation with human papillomavirus infection in cervical carcinoma.
Du, C.-W., & Wang, Y. (2012) · PubMed · Cited by 19 · see citing works
Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma.
Algazi, A. P., Muthukumar, A. H., O'Brien, K., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.9068 · Cited by 14 · see citing works
PI3K Inhibitor Improves PFS in BELLE-2 Trial
(2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-nb2015-176 · Cited by 14 · see citing works
Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.
Kalinsky, K. M., Sparano, J., Kim, M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.tps147 · Cited by 10 · see citing works
Self-citation
The big and the small picture
Heinrichs, A. A. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2176 · Cited by 8 · see citing works
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.
Banerji, U., Dean, E. J., Fidalgo, J. A. P., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.33.15_suppl.2500 · Cited by 6 · see citing works
Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.
Kalinsky, K. M., Sparano, J. A., Andreopoulou, E., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.2613 · Cited by 6 · see citing works
Self-citation

Flagged first, then by citations

Research works printed but not linked: 5

Blachly JS, Baiocchi RA. Targeting the PI3-kinase (PI3K), AKT, and mTOR axis in lymphoma. Br J Hematol 2014; 167: 19-32.
Dunbar ME, Wysolmerski JJ. Mammary ductal and alveolar development: lesson learned from genetically manipulated mice. Microsc Res Tech 2001; 52: 163-70.
P. S. Mundi et al. 954 Br J Clin Pharmacol (2016) 82 943-956 13652125, 2016, 4, 40 · DOI
Perou C; Cancer Genome Atlas Network. Comprehensive portraits of human breast tumors. Nature 2012; 490: 61-70.
Sale EM, Sale GJ. Protein kinase B: signaling roles and therapeutic targets. Cell Mol Life Sci 2008; 65: 113-27.

Sorted by citations

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Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0056-y · Cited by 333 · see citing works
Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer
Chen, R., Lai, L. A., Sullivan, Y., Wong, M., Wang, L., Riddell, J., Jung, L., Pillarisetty, V. G., Brentnall, T. A., & Pan, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-08436-6 · Cited by 92 · see citing works
GSK-3 as a novel prognostic indicator in leukemia
Ruvolo, P. P. (2017) · Advances in Biological Regulation · doi:10.1016/j.jbior.2017.05.001 · Cited by 39 · see citing works

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Wang, Y., Wang, P., & Zhao, W. (2021) · Journal of Biosciences and Medicines · doi:10.4236/jbm.2021.910008 · Cited by 1 · see citing works
FoxO Transcription Factors Promote AKT Ser473 Phosphorylation and Renal Tumor Growth in Response to Pharmacologic Inhibition of the PI3K–AKT Pathway
Lin, A., Piao, H.-L., Li, Z., Sarbassov, D. D., Ma, L., & Gan, B. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1729 · Cited by 148 · see citing works
Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects
Dufour, M., Dormond-Meuwly, A., Pythoud, C., Demartines, N., & Dormond, O. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.07.014 · Cited by 21 · see citing works
Virtual Docking Screening and QSAR Studies to Explore PI3K and mTOR Inhibitors Acting on AKT in Cancers
Kandoussi, I., Benherrif, O., Lakhlili, W., et al. (2020) · Journal of Cancer Science and Clinical Therapeutics · doi:10.26502/jcsct.5079099 · Cited by 1 · see citing works
Solanine Interferes With AKT/p-AKT and PI3K/ p-PI3K to Inhibit HIF and Destroy Cell Energy MetabolismPreprint
Wang, P., & Wang, Y. (2021) · Research Square · doi:10.21203/rs.3.rs-663150/v1

Authors: Mundi, P. S., Sachdev, J., McCourt, C., & Kalinsky, K.
Affiliations: Columbia University Irving Medical Center (US)
Translational Genomics Research Institute (US)
Washington University in St. Louis (US)
Corresponding author: Kalinsky, Kevin
ORCID: Mundi, Prabhjot S.
Sachdev, Jasgit
McCourt, Carolyn
Kalinsky, Kevin
Venue: British Journal of Clinical Pharmacology
Publisher: Wiley
Published: 2016-06-27
Volume: 82
Issue: 4
Pages: 943-956
ISSN: 0306-5251 (ISSN-L)
1365-2125
DOI: 10.1111/bcp.13021
PMC: PMC5137819
OpenAlex: W2397963384
Cited by: 272
References: 109
Citations by year: 2026: 16 · 2025: 24 · 2024: 29 · 2023: 19 · 2022: 28 · 2021: 29 · 2020: 45 · 2019: 29 · 2018: 25 · 2017: 22 · 2016: 6
FWCI: 2.44
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: British Journal of Clinical Pharmacology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords: Akt, PI3K/Akt signaling, cancer, carcinogenesis, AKT inhibitors, targeted cancer therapy, PI3K mutations, copy number alterations, epigenetic regulation, cell proliferation and survival, programmed cell death
MeSH terms: Proto-Oncogene Mas, Animals, Humans, Neoplasms, Signal Transduction, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Molecular Targeted Therapy, Carcinogenesis

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

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