Benefits of mTOR kinase targeting in oncology: Pre-clinical evidence with AZD8055

Biochemical Society Transactions

Volumn 39, Issue 2, 2011, Pages 456-459

  Marshall, Gayle ^a   Howard, Zoe ^a   Dry, Jonathan ^a   Fenton, Sarah ^a   Heathcote, Dan ^a   Gray, Neil ^a   Keen, Heather ^a   Logie, Armelle ^a   Holt, Sarah ^a   Smith, Paul ^a   Guichard, Sylvie M ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Akt; AZD8055; Mammalian target of rapamycin complex (mTORC); Mammalian target of rapamycin kinase (mTOR kinase); Oncology

Indexed keywords

ARRRY 142866; ARRY 142866; AZD 8055; BIOLOGICAL MARKER; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PP 242; RAPAMYCIN; RAPAMYCIN DERIVATIVE; SELUMETINIB; TEMSIROLIMUS; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; AUTOPHAGY; CANCER PATIENT; CELL CYCLE PROGRESSION; CELL CYCLE REGULATION; CELL DEATH; CLEAR CELL CARCINOMA; COMPARATIVE STUDY; DRUG SCREENING; DRUG TARGETING; GLIOBLASTOMA; GROWTH INHIBITION; HUMAN; KIDNEY CARCINOMA; LUNG NON SMALL CELL CANCER; MANTLE CELL LYMPHOMA; MITOSIS INHIBITION; MULTIPLE MYELOMA; NONHUMAN; ONCOLOGY; PHENOTYPIC VARIATION; PRIORITY JOURNAL; REVIEW; VON HIPPEL LINDAU DISEASE;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG EVALUATION, PRECLINICAL; HUMANS; MEDICAL ONCOLOGY; MOLECULAR TARGETED THERAPY; MORPHOLINES; NEOPLASMS; PROTEIN KINASE INHIBITORS; SIROLIMUS; TOR SERINE-THREONINE KINASES;

MAMMALIA;

EID: 79953169191     PISSN: 03005127     EISSN: 14708752     Source Type: Journal    
DOI: 10.1042/BST0390456     Document Type: Review

References (14)

1. Guertin, D.A. and Sabatini, D.M. (2007) Defining the role of mTOR in cancer. Cancer Cell 12, 9-22 (Pubitemid 47001784)
2. Cloughesy, T.F., Yoshimoto, K., Nghiemphu, P., Brown, K., Dang, J., Zhu, S., Hsueh, Y., Chen, Y., Wang, W., Youngkin, D. et al. (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 5, e8
3. Gibbons, J.J., Abraham, R.T. and Yu, K. (2009) Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin. Oncol. 36 (Suppl. 3), S3-S17
4. Garcia-Martinez, J.M., Moran, J., Clarke, R.G., Gray, A., Cosulich, S.C., Chresta, C.M. and Alessi, D.R. (2009) Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem. J. 421, 29-42
5. Thoreen, C.C., Kang, S.A., Chang, J.W., Liu, Q., Zhang, J., Gao, Y., Reichling, L.J., Sim, T., Sabatini, D.M. and Gray, N.S. (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023-8032
6. Feldman, M.E., Apsel, B., Uotila, A., Loewith, R., Knight, Z.A., Ruggero, D. and Shokat, K.M. (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38
7. Chresta, C.M., Davies, B.R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S.E., Vincent, J.P., Ellston, R., Jones, D., Sini, P. et al. (2010) AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 70, 288-298
8. Hsieh, A.C., Costa, M., Zollo, O., Davis, C., Feldman, M.E., Testa, J.R., Meyuhas, O., Shokat, K.M. and Ruggero, D. (2010) Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17, 249-261
9. Jung, C.H., Ro, S.H., Cao, J., Otto, N.M. and Kim, D.H. (2010) mTOR regulation of autophagy. FEBS Lett. 584, 1287-1295
10. Mammucari, C., Schiaffino, S. and Sandri, M. (2008) Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy 4, 524-526 (Pubitemid 351705153)
11. Sini, P., James, D., Chresta, C. and Guichard, S. (2010) Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy 6, 553-554
12. Keen, H., Ricketts, S.-A., Bales, J., Shannon, A., Logie, A., Odedra, R., Wedge, S. and Guichard, S. (2009) The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG. Mol. Cancer Ther. 8 (Suppl. 1), A225
13. Holt, S.V., Marshall, G., Logie, A., Howard, A., Fenton, S., Dry, J., James, D., Brown, E., Wilkinson, R.W. and Guichard, S.M. (2010) The mTOR kinase inhibitor AZD8055 induces cell death in Her2+ tumours partially or intrinsically resistant to ErbB2 inhibitors. 22nd EORTC-NCI-AACR symposium on "Molecular Targets and Cancer Therapeutics", Berlin, Germany, 16-19 November 2010, Abstract 157
14. Howard, Z., Dry, J., Marshall, G., Curtis, N., Guichard, S. and Smith, P. (2010) The combination of AZD8055 and selumetinib (AZD6244, ARRY-142886) is synergistic in a subset of non small cell lung cancer cell lines with co-dependency to the MEK and mTOR pathways. NCRI Conference, Liverpool, U.K., 7-10 November 2010