User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.

Primary tabs

Seront, Emmanuel [UCL] Pinto Fernandez, Adan [UCL] Bouzin, Caroline [UCL] Bertrand, Luc [UCL] Machiels, Jean-Pascal [UCL] Feron, Olivier [UCL]

BACKGROUND: Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment. METHODS: Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors. RESULTS: Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo. CONCLUSION: Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "The British journal of cancer" - Vol. 109, no. 6, p. 1586-1592 (2013)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
issn 0007-0920
e-issn 1532-1827
Publication status Publié
Affiliations UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie
UCL - (SLuc) Unité d'oncologie médicale
UCL - (SLuc) Centre du cancer
UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire
Links
  1. Aveyard J S, Skilleter A, Habuchi T, Knowles M A, Somatic mutation of PTEN in bladder carcinoma, 10.1038/sj.bjc.6690439
  2. Brunn GJ, EMBO J, 15, 5256 (1996)
  3. Chandarlapaty Sarat, Sawai Ayana, Scaltriti Maurizio, Rodrik-Outmezguine Vanessa, Grbovic-Huezo Olivera, Serra Violeta, Majumder Pradip K., Baselga Jose, Rosen Neal, AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity, 10.1016/j.ccr.2010.10.031
  4. Cloughesy Tim F, Yoshimoto Koji, Nghiemphu Phioanh, Brown Kevin, Dang Julie, Zhu Shaojun, Hsueh Teli, Chen Yinan, Wang Wei, Youngkin David, Liau Linda, Martin Neil, Becker Don, Bergsneider Marvin, Lai Albert, Green Richard, Oglesby Tom, Koleto Michael, Trent Jeff, Horvath Steve, Mischel Paul S, Mellinghoff Ingo K, Sawyers Charles L, Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma, 10.1371/journal.pmed.0050008
  5. Engelman Jeffrey A., Targeting PI3K signalling in cancer: opportunities, challenges and limitations, 10.1038/nrc2664
  6. Feldman Morris E., Shokat Kevan M., New Inhibitors of the PI3K-Akt-mTOR Pathway: Insights into mTOR Signaling from a New Generation of Tor Kinase Domain Inhibitors (TORKinibs), Current Topics in Microbiology and Immunology (2010) ISBN:9783642148156 p.241-262, 10.1007/82_2010_64
  7. Figlin Robert A., de Souza Paul, McDermott David, Dutcher Janice P., Berkenblit Anna, Thiele Alexandra, Krygowski Mizue, Strahs Andrew, Feingold Jay, Boni Joseph, Hudes Gary, Analysis of PTEN and HIF-1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-α, 10.1002/cncr.24438
  8. Fleming Gini F., Ma Cynthia X., Huo Dezheng, Sattar Husain, Tretiakova Maria, Lin L., Hahn Olwen M., Olopade F. O., Nanda R., Hoffman Philip C., Naughton M. J., Pluard Timothy, Conzen Suzanne D., Ellis Matthew J., Phase II trial of temsirolimus in patients with metastatic breast cancer, 10.1007/s10549-011-1910-7
  9. Guertin David A., Sabatini David M., Defining the Role of mTOR in Cancer, 10.1016/j.ccr.2007.05.008
  10. Hollander M. Christine, Blumenthal Gideon M., Dennis Phillip A., PTEN loss in the continuum of common cancers, rare syndromes and mouse models, 10.1038/nrc3037
  11. Javle Milind M, Shroff Rachna T, Xiong Henry, Varadhachary Gauri A, Fogelman David, Reddy Shrikanth A, Davis Darren, Zhang Yujian, Wolff Robert A, Abbruzzese James L, Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies, 10.1186/1471-2407-10-368
  12. Laplante Mathieu, Sabatini David M., mTOR Signaling in Growth Control and Disease, 10.1016/j.cell.2012.03.017
  13. Maehama Tomohiko, Dixon Jack E., The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate, 10.1074/jbc.273.22.13375
  14. Markman Ben, Dienstmann Rodrigo, Tabernero Josep, Targeting the PI3K/Akt/mTOR Pathway – Beyond Rapalogs, 10.18632/oncotarget.188
  15. Meric-Bernstam Funda, Gonzalez-Angulo Ana Maria, Targeting the mTOR Signaling Network for Cancer Therapy, 10.1200/jco.2008.20.0766
  16. Neshat M. S., Mellinghoff I. K., Tran C., Stiles B., Thomas G., Petersen R., Frost P., Gibbons J. J., Wu H., Sawyers C. L., Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR, 10.1073/pnas.171076798
  17. Nicholson Karleen M, Anderson Neil G, The protein kinase B/Akt signalling pathway in human malignancy, 10.1016/s0898-6568(01)00271-6
  18. O'Reilly Kathryn E., Rojo Fredi, She Qing-Bai, Solit David, Mills Gordon B., Smith Debra, Lane Heidi, Hofmann Francesco, Hicklin Daniel J., Ludwig Dale L., Baselga Jose, Rosen Neal, mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt, 10.1158/0008-5472.can-05-2925
  19. Oza Amit M., Elit Laurie, Tsao Ming-Sound, Kamel-Reid Suzanne, Biagi Jim, Provencher Diane Michele, Gotlieb Walter H., Hoskins Paul J., Ghatage Prafull, Tonkin Katia S., Mackay Helen J., Mazurka John, Sederias Joana, Ivy Percy, Dancey Janet E., Eisenhauer Elizabeth A., Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group, 10.1200/jco.2010.34.1578
  20. Platt F. M., Hurst C. D., Taylor C. F., Gregory W. M., Harnden P., Knowles M. A., Spectrum of Phosphatidylinositol 3-Kinase Pathway Gene Alterations in Bladder Cancer, 10.1158/1078-0432.ccr-09-0898
  21. Podsypanina K., Lee R. T., Politis C., Hennessy I., Crane A., Puc J., Neshat M., Wang H., Yang L., Gibbons J., Frost P., Dreisbach V., Blenis J., Gaciong Z., Fisher P., Sawyers C., Hedrick-Ellenson L., Parsons R., An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice, 10.1073/pnas.171060098
  22. Qian C.-N., Furge K. A., Knol J., Huang D., Chen J., Dykema K. J., Kort E. J., Massie A., Khoo S. K., Vanden Beldt K., Resau J. H., Anema J., Kahnoski R. J., Morreau H., Camparo P., Comperat E., Sibony M., Denoux Y., Molinie V., Vieillefond A., Eng C., Williams B. O., Teh B. T., Activation of the PI3K/AKT Pathway Induces Urothelial Carcinoma of the Renal Pelvis: Identification in Human Tumors and Confirmation in Animal Models, 10.1158/0008-5472.can-09-1689
  23. Ramaswamy S., Nakamura N., Vazquez F., Batt D. B., Perera S., Roberts T. M., Sellers W. R., Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway, 10.1073/pnas.96.5.2110
  24. Seront E., Rottey S., Sautois B., Kerger J., D'Hondt L. A., Verschaeve V., Canon J.-L., Dopchie C., Vandenbulcke J. M., Whenham N., Goeminne J. C., Clausse M., Verhoeven D., Glorieux P., Branders S., Dupont P., Schoonjans J., Feron O., Machiels J.-P., Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers, 10.1093/annonc/mds057
  25. Shi Y, Cancer Res, 62, 5027 (2002)
  26. Stambolic Vuk, Suzuki Akira, de la Pompa José Luis, Brothers Greg M, Mirtsos Christine, Sasaki Takehiko, Ruland Jurgen, Penninger Josef M, Siderovski David P, Mak Tak W, Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN, 10.1016/s0092-8674(00)81780-8
  27. Steelman L S, Navolanic P M, Sokolosky M L, Taylor J R, Lehmann B D, Chappell W H, Abrams S L, Wong E W T, Stadelman K M, Terrian D M, Leslie N R, Martelli A M, Stivala F, Libra M, Franklin R A, McCubrey J A, Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors, 10.1038/onc.2008.49
  28. Sun Shi-Yong, Rosenberg Laura M., Wang Xuerong, Zhou Zhongmei, Yue Ping, Fu Haian, Khuri Fadlo R., Activation of Akt and eIF4E Survival Pathways by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition, 10.1158/0008-5472.can-05-0917
  29. Tsuruta Hiroshi, Kishimoto Hiroyuki, Sasaki Takehiko, Horie Yasuo, Natsui Miyuki, Shibata Yoshiko, Hamada Koichi, Yajima Nobuyuki, Kawahara Koichi, Sasaki Masato, Tsuchiya Norihiko, Enomoto Katsuhiko, Mak Tak Wah, Nakano Toru, Habuchi Tomonori, Suzuki Akira, Hyperplasia and Carcinomas in Pten-Deficient Mice and Reduced PTEN Protein in Human Bladder Cancer Patients, 10.1158/0008-5472.can-05-4627
  30. Vilar E., Perez-Garcia J., Tabernero J., Pushing the Envelope in the mTOR Pathway: The Second Generation of Inhibitors, 10.1158/1535-7163.mct-10-0905
  31. Weigelt B, Warne P H, Downward J, PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs, 10.1038/onc.2011.42
  32. Yohn Nicole L, Bingaman Caitlyn N, DuMont Ashley L, Yoo Lina I, Phosphatidylinositol 3'-kinase, mTOR, and Glycogen synthase kinase-3β mediated regulation of p21 in human urothelial carcinoma cells, 10.1186/1471-2490-11-19
Bibliographic reference Seront, Emmanuel ; Pinto Fernandez, Adan ; Bouzin, Caroline ; Bertrand, Luc ; Machiels, Jean-Pascal ; et. al. PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.. In: The British journal of cancer, Vol. 109, no. 6, p. 1586-1592 (2013)
Permanent URL http://hdl.handle.net/2078.1/136958