Targeting the PI3K/AKT/mTOR Pathway in Bladder Cancer

  • Anuja Sathe
  • Roman NawrothEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1655)


The PI3K/AKT/mTOR signaling pathway shows frequent molecular alterations and increased activity in cancer. Given its role in the regulation of cell growth, survival and metastasis, molecules within this pathway are promising targets for pharmacologic intervention. Metastatic bladder cancer (BLCA) continues to have few treatment options. Although various molecular alterations in PI3K/AKT/mTOR signaling have been described in BLCA, clinical trials with small molecule inhibitors have not met their endpoints. In this article, we summarize results from preclinical studies and clinical trials that examined PI3K pathway inhibitors in BLCA focusing on technical challenges that might result in contradictory findings in preclinical studies. Based on published data from our group, we also address challenges that need to be overcome to optimize PI3K inhibition in BLCA and enable its successful translation into the clinic.

Key words

Bladder cancer PI3K/AKT/mTOR 


  1. 1.
    Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619. doi: 10.1038/nrg1879 CrossRefPubMedGoogle Scholar
  2. 2.
    Franke TF (2008) PI3K/Akt: getting it right matters. Oncogene 27(50):6473–6488. doi: 10.1038/onc.2008.313 CrossRefPubMedGoogle Scholar
  3. 3.
    Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(Pt 20):3589–3594. doi: 10.1242/jcs.051011 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N (2006) mTOR, translation initiation and cancer. Oncogene 25(48):6416–6422. doi: 10.1038/sj.onc.1209888 CrossRefPubMedGoogle Scholar
  5. 5.
    Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507(7492):315–322. doi: 10.1038/nature12965 CrossRefGoogle Scholar
  6. 6.
    Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, Zabor EC, Janakiraman M, Garcia-Grossman IR, Heguy A, Viale A, Bochner BH, Reuter VE, Bajorin DF, Milowsky MI, Taylor BS, Solit DB (2013) Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol 31(25):3133–3140. doi: 10.1200/JCO.2012.46.5740 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA (2009) Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res 15(19):6008–6017. doi: 10.1158/1078–0432.CCR-09-0898. [pii]CrossRefPubMedGoogle Scholar
  8. 8.
    Calderaro J, Rebouissou S, de Koning L, Masmoudi A, Herault A, Dubois T, Maille P, Soyeux P, Sibony M, de la Taille A, Vordos D, Lebret T, Radvanyi F, Allory Y (2014) PI3K/AKT pathway activation in bladder carcinogenesis. Int J Cancer 134(8):1776–1784. doi: 10.1002/ijc.28518 CrossRefPubMedGoogle Scholar
  9. 9.
    Cappellen D, Gil Diez de Medina S, Chopin D, Thiery JP, Radvanyi F (1997) Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene 14(25):3059–3066. doi: 10.1038/sj.onc.1201154 CrossRefPubMedGoogle Scholar
  10. 10.
    Aveyard JS, Skilleter A, Habuchi T, Knowles MA (1999) Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80(5–6):904–908. doi: 10.1038/sj.bjc.6690439 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tsuruta H, Kishimoto H, Sasaki T, Horie Y, Natsui M, Shibata Y, Hamada K, Yajima N, Kawahara K, Sasaki M, Tsuchiya N, Enomoto K, Mak TW, Nakano T, Habuchi T, Suzuki A (2006) Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients. Cancer Res 66(17):8389–8396. doi: 10.1158/0008-5472.CAN-05-4627 CrossRefPubMedGoogle Scholar
  12. 12.
    Knowles MA, Habuchi T, Kennedy W, Cuthbert-Heavens D (2003) Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res 63(22):7652–7656PubMedGoogle Scholar
  13. 13.
    Askham JM, Platt F, Chambers PA, Snowden H, Taylor CF, Knowles MA (2010) AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K. Oncogene 29(1):150–155. doi: 10.1038/onc.2009.315 CrossRefPubMedGoogle Scholar
  14. 14.
    Alfred Witjes J, Lebret T, Comperat EM, Cowan NC, De Santis M, Bruins HM, Hernandez V, Espinos EL, Dunn J, Rouanne M, Neuzillet Y, Veskimae E, van der Heijden AG, Gakis G, Ribal MJ (2017) Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 71:462–475. doi: 10.1016/j.eururo.2016.06.020 CrossRefPubMedGoogle Scholar
  15. 15.
    Ratner M (2016) Genentech's PD-L1 agent approved for bladder cancer. Nat Biotechnol 34(8):789–790. doi: 10.1038/nbt0816-789 CrossRefPubMedGoogle Scholar
  16. 16.
    Dienstmann R, Rodon J, Serra V, Tabernero J (2014) Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 13(5):1021–1031. doi: 10.1158/1535-7163.MCT-13-0639 CrossRefPubMedGoogle Scholar
  17. 17.
    Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15(3):155–162. doi: 10.1038/nrm3757 CrossRefPubMedGoogle Scholar
  18. 18.
    Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156. doi: 10.1038/nrd4204 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nawroth R, Stellwagen F, Schulz WA, Stoehr R, Hartmann A, Krause BJ, Gschwend JE, Retz M (2011) S6K1 and 4E-BP1 are independent regulated and control cellular growth in bladder cancer. PLoS One 6(11):e27509. doi: 10.1371/journal.pone.0027509 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chiong E, Lee IL, Dadbin A, Sabichi AL, Harris L, Urbauer D, McConkey DJ, Dickstein RJ, Cheng T, Grossman HB (2011) Effects of mTOR inhibitor everolimus (RAD001) on bladder cancer cells. Clin Cancer Res 17(9):2863–2873. doi: 10.1158/1078-0432.CCR-09-3202 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lin JF, Lin YC, Yang SC, Tsai TF, Chen HE, Chou KY, Hwang TI (2016) Autophagy inhibition enhances RAD001-induced cytotoxicity in human bladder cancer cells. Drug Des Devel Ther 10:1501–1513. doi: 10.2147/DDDT.S95900 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kyou Kwon J, Kim SJ, Hoon Kim J, Mee Lee K, Ho Chang I (2014) Dual inhibition by S6K1 and Elf4E is essential for controlling cellular growth and invasion in bladder cancer. Urol Oncol 32(1):51 e27-35. doi: 10.1016/j.urolonc.2013.08.005 PubMedGoogle Scholar
  23. 23.
    Guo Y, Chekaluk Y, Zhang J, Du J, Gray NS, Wu CL, Kwiatkowski DJ (2013) TSC1 involvement in bladder cancer: diverse effects and therapeutic implications. J Pathol 230(1):17–27. doi: 10.1002/path.4176 CrossRefPubMedGoogle Scholar
  24. 24.
    Seront E, Pinto A, Bouzin C, Bertrand L, Machiels JP, Feron O (2013) PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation. Br J Cancer 109(6):1586–1592. doi: 10.1038/bjc.2013.505 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023–8032. doi: 10.1074/jbc.M900301200 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38. doi: 10.1371/journal.pbio.1000038 CrossRefPubMedGoogle Scholar
  27. 27.
    Efeyan A, Sabatini DM (2010) mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 22(2):169–176. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  28. 28.
    Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338(6104):221. doi: 10.1126/science.1226344 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Seront E, Rottey S, Sautois B, Kerger J, D'Hondt LA, Verschaeve V, Canon JL, Dopchie C, Vandenbulcke JM, Whenham N, Goeminne JC, Clausse M, Verhoeven D, Glorieux P, Branders S, Dupont P, Schoonjans J, Feron O, Machiels JP (2012) 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. Ann Oncol 23(10):2663–2670. doi: 10.1093/annonc/mds057 CrossRefPubMedGoogle Scholar
  30. 30.
    Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, Elfiky AA, Taplin ME, Stack EC, Signoretti S, Loda M, Shapiro GI, Sabatini DM, Lander ES, Gabriel SB, Kantoff PW, Garraway LA, Rosenberg JE (2014) Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov 4(5):546–553. doi: 10.1158/2159-8290.CD-13-0353 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sathe A, Guerth F, Cronauer MV, Heck MM, Thalgott M, Gschwend JE, Retz M, Nawroth R (2014) Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy. Br J Cancer 111(11):2103–2113. doi: 10.1038/bjc.2014.534 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dickstein RJ, Nitti G, Dinney CP, Davies BR, Kamat AM, McConkey DJ (2012) Autophagy limits the cytotoxic effects of the AKT inhibitor AZ7328 in human bladder cancer cells. Cancer Biol Ther 13(13):1325–1338. doi: 10.4161/cbt.21793 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ross RL, McPherson HR, Kettlewell L, Shnyder SD, Hurst CD, Alder O, Knowles MA (2016) PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. BMC Cancer 16:553. doi: 10.1186/s12885-016-2570-0 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Gopa Iyer CMT, Garcia-Grossman IR, Scott SN, Boyd ME, McCoy AS, Berger MF, Al-Ahmadie H, Solit DB, Rosenberg JE, Bajorin DF (2015) Phase 2 study of the pan-isoform PI3 kinase inhibitor BKM120 in metastatic urothelial carcinoma patients. J Clin Oncol 33(suppl 7):abstr 324CrossRefGoogle Scholar
  35. 35.
    Moon du G, Lee SE, Oh MM, Lee SC, Jeong SJ, Hong SK, Yoon CY, Byun SS, Park HS, Cheon J (2014) NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells. Int J Oncol 45(3):1027–1035. doi: 10.3892/ijo.2014.2505 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Li JR, Cheng CL, Yang CR, Ou YC, Wu MJ, Ko JL (2013) Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin NVP-BEZ235 effectively inhibits cisplatin-resistant urothelial cancer cell growth through autophagic flux. Toxicol Lett 220(3):267–276. doi: 10.1016/j.toxlet.2013.04.021 CrossRefPubMedGoogle Scholar
  37. 37.
    Seront E, Rottey S, Filleul B, Glorieux P, Goeminne JC, Verschaeve V, Vandenbulcke JM, Sautois B, Boegner P, Gillain A, van Maanen A, Machiels JP (2016) Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma. BJU Int 118(3):408–415. doi: 10.1111/bju.13415 CrossRefPubMedGoogle Scholar
  38. 38.
    Munster P, Aggarwal R, Hong D, Schellens JH, van der Noll R, Specht J, Witteveen PO, Werner TL, Dees EC, Bergsland E, Agarwal N, Kleha JF, Durante M, Adams L, Smith DA, Lampkin TA, Morris SR, Kurzrock R (2016) First-in-human phase I study of GSK2126458, an oral pan-class I phosphatidylinositol-3-kinase inhibitor, in patients with advanced solid tumor malignancies. Clin Cancer Res 22(8):1932–1939. doi: 10.1158/1078-0432.CCR-15-1665 CrossRefPubMedGoogle Scholar
  39. 39.
    Rodon J, Dienstmann R, Serra V, Tabernero J (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10(3):143–153. doi: 10.1038/nrclinonc.2013.10 CrossRefPubMedGoogle Scholar
  40. 40.
    Nassim R, Mansure JJ, Chevalier S, Cury F, Kassouf W (2013) Combining mTOR inhibition with radiation improves antitumor activity in bladder cancer cells in vitro and in vivo: a novel strategy for treatment. PLoS One 8(6):e65257. doi: 10.1371/journal.pone.0065257 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15(1):25–41. doi: 10.1038/nrc3817 CrossRefPubMedGoogle Scholar
  42. 42.
    Nickerson ML, Witte N, Im KM, Turan S, Owens C, Misner K, Tsang SX, Cai Z, Wu S, Dean M, Costello JC, Theodorescu D (2017) Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response. Oncogene 36:35–46. doi: 10.1038/onc.2016.172 CrossRefPubMedGoogle Scholar
  43. 43.
    Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jane-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi P Jr, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA (2012) The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483(7391):603–607. doi: 10.1038/nature11003 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, Ding M, Bamford S, Cole C, Ward S, Kok CY, Jia M, De T, Teague JW, Stratton MR, McDermott U, Campbell PJ (2015) COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res 43(Database issue):D805–D811. doi: 10.1093/nar/gku1075 CrossRefPubMedGoogle Scholar
  45. 45.
    Riss TL, Moravec RA, Niles AL, Duellman S, Benink HA, Worzella TJ, Minor L (2004) Cell viability assays. In: Sittampalam GS, Coussens NP, Nelson H et al (eds) Assay guidance manual. Eli Lilly & Company and the National Center for Advancing Translational Sciences, Bethesda (MD)Google Scholar
  46. 46.
    Haverty PM, Lin E, Tan J, Yu Y, Lam B, Lianoglou S, Neve RM, Martin S, Settleman J, Yauch RL, Bourgon R (2016) Reproducible pharmacogenomic profiling of cancer cell line panels. Nature 533(7603):333–337. doi: 10.1038/nature17987 CrossRefPubMedGoogle Scholar
  47. 47.
    Haibe-Kains B, El-Hachem N, Birkbak NJ, Jin AC, Beck AH, Aerts HJ, Quackenbush J (2013) Inconsistency in large pharmacogenomic studies. Nature 504(7480):389–393. doi: 10.1038/nature12831 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Boettcher M, McManus MT (2015) Choosing the right tool for the job: RNAi, TALEN, or CRISPR. Mol Cell 58(4):575–585. doi: 10.1016/j.molcel.2015.04.028 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1(3):1112–1116. doi: 10.1038/nprot.2006.179 CrossRefPubMedGoogle Scholar
  50. 50.
    Niegisch G, Retz M, Thalgott M, Balabanov S, Honecker F, Ohlmann CH, Stockle M, Bogemann M, Vom Dorp F, Gschwend J, Hartmann A, Ohmann C, Albers P (2015) Second-line treatment of advanced Urothelial cancer with paclitaxel and Everolimus in a German phase II trial (AUO trial AB 35/09). Oncology 89(2):70–78. doi: 10.1159/000376551 CrossRefPubMedGoogle Scholar
  51. 51.
    Milowsky MI, Iyer G, Regazzi AM, Al-Ahmadie H, Gerst SR, Ostrovnaya I, Gellert LL, Kaplan R, Garcia-Grossman IR, Pendse D, Balar AV, Flaherty AM, Trout A, Solit DB, Bajorin DF (2013) Phase II study of everolimus in metastatic urothelial cancer. BJU Int 112(4):462–470. doi: 10.1111/j.1464-410X.2012.11720.x CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gerullis H, Eimer C, Ecke TH, Georgas E, Freitas C, Kastenholz S, Arndt C, Heusch C, Otto T (2012) A phase II trial of temsirolimus in second-line metastatic urothelial cancer. Med Oncol 29(4):2870–2876. doi: 10.1007/s12032-012-0216-x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  1. 1.Department of Urology, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany

Personalised recommendations