Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation
详细信息 查看全文
- 作者：Emily M Fox (1)
María Gabriela Kuba (2)
Todd W Miller (3)
Barry R Davies (4)
Carlos L Arteaga (1) (5) (6) - 关键词：AKT ; ER+ breast cancer ; endocrine resistance ; IGF ; IR ; InsR
- 刊名：Breast Cancer Research
- 出版年：2013
- 出版时间：August 2013
- 年：2013
- 卷：15
- 期：4
- 全文大小：1,597 KB
- 参考文献：1. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR: Activation of AKT kinases in cancer: implications for therapeutic targeting. / Adv Cancer Res 2005, 94:29-6. CrossRef
2. Liu P, Cheng H, Roberts TM, Zhao JJ: Targeting the phosphoinositide 3-kinase pathway in cancer. / Nat Rev Drug Discov 2009, 8:627-44. CrossRef
3. Miller TW, Rexer BN, Garrett JT, Arteaga CL: Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. / Breast Cancer Res 2011, 13:224. CrossRef
4. Network CGA: Comprehensive molecular portraits of human breast tumours. / Nature 2012, 490:61-0. CrossRef
5. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE: A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. / Nature 2007, 448:439-44. CrossRef
6. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. / Lancet Oncol 2008, 9:45-3. CrossRef
7. Arpino G, Green SJ, Allred DC, Lew D, Martino S, Osborne CK, Elledge RM: HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. / Clin Cancer Res 2004, 10:5670-676. CrossRef
8. De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G, D'Agostino D, Caputo F, Cancello G, Montagna E, Malorni L, Zinno L, Lauria R, Bianco AR, De Placido S: A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. / Clin Cancer Res 2005, 11:4741-748. CrossRef
9. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, Garcia-Echeverria C, Shyr Y, Arteaga CL: Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. / J Clin Invest 2010, 120:2406-413. CrossRef
10. Miller TW, Balko JM, Arteaga CL: Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. / J Clin Oncol 2011, 29:4452-461. CrossRef
11. Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, Lindsley CW, Arteaga CL: 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, 69:4192-201. CrossRef
12. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H: Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. / J Biol Chem 2001, 276:9817-824. CrossRef
13. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, Parker JS, Miller MA, Huntsman DG, Lin L, Snider J, Davies SR, Olson JA jr, Watson MA, Saporita A, Weber JD, Ellis MJ: PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. / Cancer Res 2009, 69:3955-962. CrossRef
14. Block M, Grundker C, Fister S, Kubin J, Wilkens L, Mueller MD, Hemmerlein B, Emons G, Gunthert AR: Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine and analogs of gonadotropin-releasing hormone I and II to overcome tamoxifen resistance in breast cancer cells. / Int J Oncol 2012, 41:1845-854.
15. Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, Ricketts SA, Cross D, Cosulich SC, Chresta CM, Page K, Yates J, Lane C, Watson R, Luke R, Ogilvie DJ, Pass M: Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity and Correlation of Monotherapy Activity with Genetic Background. / Mol Cancer Ther 2012, 11:873-87. CrossRef
16. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC, Kung AL: Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. / Cancer Cell 2004, 5:221-30. CrossRef
17. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chene P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, Garcia-Echeverria C, Sellers WR, Voliva CF: Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. / Mol Cancer Ther 2012, 11:317-28. CrossRef
18. Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E: Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. / Clin Cancer Res 2007, 13:1576-583. CrossRef
19. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, Rooney C, Coleman T, Baker D, Mellor MJ, Brooks AN, Klinowska T: AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. / Cancer Res 2012, 72:2045-056. CrossRef
20. Okuzumi T, Fiedler D, Zhang C, Gray DC, Aizenstein B, Hoffman R, Shokat KM: Inhibitor hijacking of Akt activation. / Nat Chem Biol 2009, 5:484-93. CrossRef
21. Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, de Plater L, Guyader C, De Pinieux G, Judde JG, Rebucci M, Tran-Perennou C, Sastre-Garau X, Sigal-Zafrani B, Delattre O, Dieras V, Poupon MF: A new model of patient tumor-derived breast cancer xenografts for preclinical assays. / Clin Cancer Res 2007, 13:3989-998. CrossRef
22. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL: Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. / Proc Natl Acad Sci USA 2012, 109:2718-723. CrossRef
23. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N: AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. / Cancer Cell 2011, 19:58-1. CrossRef
24. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N: mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. / Cancer Discov 2011, 1:248-59. CrossRef
25. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM: Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. / J Med Chem 2004, 47:6658-661. CrossRef
26. Green TP, Fennell M, Whittaker R, Curwen J, Jacobs V, Allen J, Logie A, Hargreaves J, Hickinson DM, Wilkinson RW, Elvin P, Boyer B, Carragher N, Ple PA, Bermingham A, Holdgate GA, Ward WH, Hennequin LF, Davies BR, Costello GF: Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. / Mol Oncol 2009, 3:248-61. CrossRef
27. Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Martiny-Baron G, Ruetz S, Hofmann F: In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. / Cancer Cell 2004, 5:231-39. CrossRef
28. Park WS, Heo WD, Whalen JH, O'Rourke NA, Bryan HM, Meyer T, Teruel MN: Comprehensive identification of PIP3-regulated PH domains from C. elegans to H. sapiens by model prediction and live imaging. / Mol Cell 2008, 30:381-92. CrossRef
29. Pandini G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y, Siddle K, Goldfine ID, Belfiore A: Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. / Clin Cancer Res 1999, 5:1935-944.
30. Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfeld RG: Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. / Int J Biochem Cell Biol 1996, 28:619-37. CrossRef
31. Yee D, Lee AV: Crosstalk between the insulin-like growth factors and estrogens in breast cancer. / J Mammary Gland Biol Neoplasia 2000, 5:107-15. CrossRef
32. Myatt SS, Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. / Nat Rev Cancer 2007, 7:847-59. CrossRef
33. Barthel A, Schmoll D, Unterman TG: FoxO proteins in insulin action and metabolism. / Trends Endocrinol Metab 2005, 16:183-89. CrossRef
34. Zou Y, Tsai WB, Cheng CJ, Hsu C, Chung YM, Li PC, Lin SH, Hu MC: Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis. / Breast Cancer Res 2008, 10:R21. CrossRef
35. Guo S, Sonenshein GE: Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. / Mol Cell Biol 2004, 24:8681-690. CrossRef
36. Morelli C, Lanzino M, Garofalo C, Maris P, Brunelli E, Casaburi I, Catalano S, Bruno R, Sisci D, Ando S: Akt2 inhibition enables the forkhead transcription factor FoxO3a to have a repressive role in estrogen receptor alpha transcriptional activity in breast cancer cells. / Mol Cell Biol 2010, 30:857-70. CrossRef
37. Zhao HH, Herrera RE, Coronado-Heinsohn E, Yang MC, Ludes-Meyers JH, Seybold-Tilson KJ, Nawaz Z, Yee D, Barr FG, Diab SG, Brown PH, Fuqua SA, Osborne CK: Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. / J Biol Chem 2001, 276:27907-7912. CrossRef
38. Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ: Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family. / J Biol Chem 2001, 276:33554-3560. CrossRef
39. Wong C, Wang X, Smith D, Reddy K, Chen S: AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies. / Breast Cancer Res Treat 2012, 134:671-81. CrossRef
40. Tokunaga E, Kimura Y, Oki E, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Baba H, Maehara Y: Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. / Int J Cancer 2006, 118:284-89. CrossRef
41. Fox EM, Miller TW, Balko JM, Kuba MG, Sanchez V, Smith RA, Liu S, Gonzalez-Angulo AM, Mills GB, Ye F, Shyr Y, Manning HC, Buck E, Arteaga CL: A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. / Cancer Res 2011, 71:6773-784. CrossRef
42. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A: FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. / Cancer Res 2010, 70:2085-094. CrossRef - 作者单位：Emily M Fox (1)
María Gabriela Kuba (2)
Todd W Miller (3)
Barry R Davies (4)
Carlos L Arteaga (1) (5) (6)
1. Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Ave, 777 PRB, Nashville, TN, 37232-6307, USA
2. Department of Pathology, Microbiology & Immunology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Ave, 777 PRB, Nashville, TN, 37232-6307, USA
3. Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, One Medical Center Drive, HB-7936, Lebanon, NH, 03756, USA
4. Oncology Innovative Medicine, AstraZeneca, Alderley Park, Macclesfield, SK0 4TG, UK
5. Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Ave, 777 PRB, Nashville, TN, 37232-6307, USA
6. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Ave, 777 PRB, Nashville, TN, 37232-6307, USA - ISSN：1465-5411
文摘
Introduction Estrogen receptor α-positive (ER+) breast cancers adapt to hormone deprivation and acquire resistance to antiestrogen therapies. Upon acquisition of hormone independence, ER+ breast cancer cells increase their dependence on the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We examined the effects of AKT inhibition and its compensatory upregulation of insulin-like growth factor (IGF)-I/InsR signaling in ER+ breast cancer cells with acquired resistance to estrogen deprivation. Methods Inhibition of AKT using the catalytic inhibitor AZD5363 was examined in four ER+ breast cancer cell lines resistant to long-term estrogen deprivation (LTED) by western blotting and proliferation assays. Feedback upregulation and activation of receptor tyrosine kinases (RTKs) was examined by western blotting, real-time qPCR, ELISAs, membrane localization of AKT PH-GFP by immunofluorescence and phospho-RTK arrays. For studies in vivo, athymic mice with MCF-7 xenografts were treated with AZD5363 and fulvestrant with either the ATP-competitive IGF-IR/InsR inhibitor AZD9362 or the fibroblast growth factor receptor (FGFR) inhibitor AZD4547. Results Treatment with AZD5363 reduced phosphorylation of the AKT/mTOR substrates PRAS40, GSK3α/β and S6K while inducing hyperphosphorylation of AKT at T308 and S473. Inhibition of AKT with AZD5363 suppressed growth of three of four ER+ LTED lines and prevented emergence of hormone-independent MCF-7, ZR75-1 and MDA-361 cells. AZD5363 suppressed growth of MCF-7 xenografts in ovariectomized mice and a patient-derived luminal B xenograft unresponsive to tamoxifen or fulvestrant. Combined treatment with AZD5363 and fulvestrant suppressed MCF-7 xenograft growth better than either drug alone. Inhibition of AKT with AZD5363 resulted in upregulation and activation of RTKs, including IGF-IR and InsR, upregulation of FoxO3a and ERα mRNAs as well as FoxO- and ER-dependent transcription of IGF-I and IGF-II ligands. Inhibition of IGF-IR/InsR or PI3K abrogated AKT PH-GFP membrane localization and T308 P-AKT following treatment with AZD5363. Treatment with IGFBP-3 blocked AZD5363-induced P-IGF-IR/InsR and T308 P-AKT, suggesting that receptor phosphorylation was dependent on increased autocrine ligands. Finally, treatment with the dual IGF-IR/InsR inhibitor AZD9362 enhanced the anti-tumor effect of AZD5363 in MCF-7/LTED cells and MCF-7 xenografts in ovariectomized mice devoid of estrogen supplementation. Conclusions These data suggest combinations of AKT and IGF-IR/InsR inhibitors would be an effective treatment strategy against hormone-independent ER+ breast cancer.