Synergistic anti-tumor effects of RAD001 with MEK inhibitors in neuroendocrine tumors: A potential mechanism of therapeutic limitation of mTOR inhibitor

Molecular and Cellular Endocrinology

Volumn 350, Issue 1, 2012, Pages 99-106

  Iida, Shinya ^a   Miki, Yasuhiro ^a   Ono, Katsuhiko ^a   Akahira, Jun ichi ^a   Nakamura, Yasuhiro ^a   Suzuki, Takashi ^a   Sasano, Hironobu ^a  

^a TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Mammalian target of rapamycin; Mitogen activated protein kinase; Neuroendocrine tumors; Signal transduction

Indexed keywords

EVEROLIMUS; GELATINASE A; GELATINASE B; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; PROTEIN KINASE B; UO 126;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CELL ASSAY; CELL CYCLE ARREST; CELL MIGRATION; CELL PROLIFERATION; CONTROLLED STUDY; DISEASE MARKER; DNA SEQUENCE; DOWN REGULATION; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; HUMAN; HUMAN CELL; NEUROENDOCRINE TUMOR; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; TUMOR CELL CULTURE;

ANTINEOPLASTIC AGENTS; BUTADIENES; CELL CYCLE PROTEINS; CELL LINE, TUMOR; CELL MOVEMENT; CELL PROLIFERATION; CHROMOGRANIN A; DRUG SYNERGISM; GENE EXPRESSION; HUMANS; MAP KINASE KINASE KINASES; MATRIX METALLOPROTEINASE 2; MATRIX METALLOPROTEINASE 9; NEUROENDOCRINE TUMORS; NITRILES; PHOSPHOPYRUVATE HYDRATASE; PROTEIN KINASE INHIBITORS; SIROLIMUS; TOR SERINE-THREONINE KINASES; VESICULAR TRANSPORT PROTEINS;

EID: 84856034758     PISSN: 03037207     EISSN: 18728057     Source Type: Journal    
DOI: 10.1016/j.mce.2011.11.024     Document Type: Article

References (54)

1. Amato R.J., Jac J., Giessinger S., Saxena S., Willis J.P. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009, 115:2438-2446.
2. Arnold R., Simon B., Wied M. Treatment of neuroendocrine GEP tumours with somatostatin analogues. Digestion 2000, 62:84-91.
3. Bjornsti M.A., Houghton P.J. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer 2004, 4:335-348.
4. Carracedo A., Ma L., Teruya-Feldstein J., Rojo F., Salmena L., Alimonti A., Egia A., Sasaki A.T., Thomas G., Kozma S.C., Papa A., Nardella C., Cantley L.C., Baselga J., Pandolfi P.P. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 2008, 118:3065-3074.
5. Chan H.Y., Grossman A.B., Bukowski R.M. Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Adv. Ther. 2010, 27:495-511.
6. Chang Q., Chapman M.S., Miner J.N., Hedley D.W. Antitumour activity of a potent MEK inhibitor RDEA110/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenograft. BMC Cancer 2010, 10:515-526.
7. Charland S., Boucher M.J., Houde M., Rivard N. Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells. Endocrinology 2001, 142:121-128.
8. Chen J.S., Wang Q., Fu X.H., Huang X.H., Chen X.L., Cao L.Q., Chen L.Z., Tan H.X., Li W., Bi J., Zhang L.J. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol. Res. 2009, 39:177-186.
9. Chou T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 2006, 58:621-681.
10. Chou T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010, 70:440-446.
11. Chou T.C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 1984, 22:27-55.
12. Ciuffreda L., Di Sanza C., Incani U.C., Milella M. The mTOR pathway: a new target in cancer therapy. Curr. Cancer Drug Targets 2010, 10:484-495.
13. Duran I., Kortmansky J., Singh D., Hirte H., Kocha W., Goss G., Le L., Oza A., Nicklee T., Ho J., Birle D., Pond G.R., Arboine D., Dancey J., Aviel-Ronen S., Tsao M.S., Hedley D., Siu L.L. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br. J. Cancer 2006, 95:1148-1154.
14. Grozinsky-Glasberg S., Franchi G., Teng M., Leontiou C.A., Ribeiro de Oliveira A., Dalino P., Salahuddin N., Korbonits M., Grossman A.B. Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuro-endocrine tumour cell line. Neuroendocrinology 2008, 87:168-181.
15. Hartley D., Cooper G.M. Role of mTOR in the degradation of IRS-1: regulation of PP2A activity. J. Cell Biochem. 2002, 85:304-314.
16. Herbert T.P., Tee A.R., Proud C.G. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. J. Biol. Chem. 2002, 277:11591-11596.
17. Hess G., Herbrecht R., Romaguera J., Verhoef G., Crump M., Gisselbrecht C., Laurell A., Offner F., Strahs A., Berkenblit A., Hanushevsky O., Clancy J., Hewes B., Moore L., Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 2009, 27:3822-3829.
18. Hjelmeland A.B., Lattimore K.P., Fee B.E., Shi Q., Wickman S., Keir S.T., Hjelmeland M.D., Batt D., Bigner D.D., Friedman H.S., Rich J.N. The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. Mol. Cancer Ther. 2007, 6:2449-2457.
19. Hoshino R., Tanimura S., Watanabe K., Kataoka T., Kohno M. Blockade of the extracellular signal-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively activated upregulation of p27Kip1. J. Biol. Chem. 2001, 276:2686-2692.
20. Iida S., Miki Y., Ono K., Akahira J., Suzuki T., Ishida K., Watanabe M., Sasano H. Novel classification based on immunohistochemistry combined with hierarchical clustering analysis in non-functioning neuroendocrine tumor patients. Cancer Sci. 2010, 101:2278-2285.
21. Jayaraman T., Marks A.R. Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line. J. Biol. Chem. 1993, 268:25385-25388.
22. Jin N., Jiang T., Rosen D.M., Nelkin B.D., Ball D.W. Dual inhibition of mitogen-activated protein kinase kinase and mammalian target of rapamycin in differentiated and anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 2009, 94:4107-4112.
23. Johannessen C.M., Boehm J.S., Kim S.Y., Thomas S.R., Wardwell L., Johnson L.A., Emery C.M., Stransky N., Cogdill A.P., Barretina J., Caponigro G., Hieronymus H., Murray R.R., Salehi-Ashtiani K., Hill D.E., Vidal M., Zhao J.J., Yang X., Alkan O., Kim S., Harris J.L., Wilson C.J., Myer V.E., Finan P.M., Root D.E., Roberts T.M., Golub T., Flaherty K.T., Dummer R., Weber B.L., Sellers W.R., Schlegel R., Wargo J.A., Hahn W.C., Garraway L.A. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010, 468:968-973.
24. Kikade C.W., Castillo-Martin M., Puzio-Kuter A., Yan J., Foster T.H., Gao H., Sun Y., Ouyang X., Gerald W.L., Cordon-Cardo C., Abate-Shen C. Targeting AKT/mTOR and ERK/MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J. Clin. Invest. 2008, 118:3051-3064.
25. Lasithiotakis K.G., Sinnberg T.W., Schittek B., Flaherty K.T., Kulms D., Maczey E., Garbe C., Meier F.E. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J. Invest. Dermatol. 2008, 128:2013-2023.
26. Lavoie J.N., L'Allemain G.L., Brunet A., Müller R., Pouysségur J. Cyclin D1 expression is regulated positively by the p42/44MAPK and negatively by the p38/HOGMAPK pathway. J. Biol. Chem. 1996, 271:20608-20616.
27. Liang C.C., Park A.Y., Guan J.L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat. Protoc. 2007, 2:329-333.
28. Loewith R., Jacinto E., Wullschleger S., Lorberg A., Crespo J.L., Bonenfant D., Oppliger W., Jenoe P., Hall M.N. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 2002, 10:457-468.
29. Meng J., Peng H., Dai B., Guo W., Wang L., Ji L., Minna J.D., Chresta C.M., Smith P.D., Fang B., Roth J.A. High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886). Cancer Biol. Ther. 2009, 21:2073-2080.
30. Mi R., Ma J., Zhang D., Li L., Zhang H. Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model. J. Genet. Genomics 2009, 36:355-361.
31. Moreno A., Akcakanat A., Munsell M.F., Soni A., Yao J.C., Meric-Bernstam F. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr. Relat. Cancer 2008, 15:257-266.
32. Nazarian R., Shi H., Wang Q., Kong X., Koya R.C., Lee H., Chen Z., Lee M.K., Attar N., Sazegar H., Chondon T., Nelson S.F., McArthur G., Sosman J.A., Ribas A., Lo R.S. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010, 468:973-979.
33. O'Reilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., Lane H., Hofmann F., Hicklin D.J., Ludwig D.L., Baselga J., Rosen N. MTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006, 66:1500-1508.
34. Pavel, M., Peeters, M., Hörsch, D., Van Cutsem, E., öberg, K., Jehl, V., Klimovsky, J., Yao, J., 2011. Everilumus+Octreotide LAR vs placebo+Octreotide LAR in patients with advanced neuroendocrine tumors (NET): Updated results of a randomized double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2). The 8th Annual ENETS Conferences, C86.
35. Pouysségur J., Dayan F., Mazure N. Hypoxia signaling in cancer and approaches to enforce tumour regression. Nature 2006, 441:437-443.
36. Quinn L.A., Moore G.E., Morgan R.T., Woods L.K. Cell lines from human colon carcinoma with unusual cell products, double minutes, and homogeneously staining regions. Cancer Res. 1979, 39:4914-4924.
37. Reddy K.B., Krueger J.S., Kondapaka S.B., Diglio C.A. Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. Int. J. Cancer 1999, 82:268-273.
38. Reidy D.L., Tang L.H., Saltz L.B. Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors. Nat. Clin. Pract. 2009, 6:143-152.
39. Sunayama J., Matsuda K., Sato A., Tachibana K., Suzuki K., Narita Y., Shibui S., Sakurada K., Kayama T., Tomiyama A., Kitanaka C. Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenecity of glioblastoma stem-like cells. Stem Cells 2010, 28:1930-1939.
40. Thant A.A., Nawa A., Kikkawa F., Ichigotani Y., Zhang Y., Sein T.T., Amin A.R., Hamaguchi M. Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. Clin. Exp. Metastasis 2000, 18:423-428.
41. Theodoropoulou M., Zhang J., Laupheimer S., Paez-Pereda M., Erneux C., Florio T., Pagotto U., Stalla G.K. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res. 2006, 66:1576-1582.
42. Thomson A.W., Turnauist H.R., Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 2009, 9:324-337.
43. 1 progression. J. Biol. Chem. 1999, 274:4266-4272.
44. von Wichert G., Jehle P.M., Hoeflich A., Koschnick S., Dralle H., Wolf E., Wiedenmann B., Boehm B.O., Adler G., Seufferlein T. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cell. Cancer Res. 2000, 60:4573-4581.
45. Wang L., Gout I., Proud C.G. Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. J. Biol. Chem. 2001, 276:32670-32677.
46. Wang X., Hawk N., Yue P., Kauh J., Ramalingam S.S., Fu H., Khuri F.R., Sun S.Y. Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors' anticancer efficacy. Cancer Biol. Ther. 2008, 7:1952-1958.
47. Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism. Cell 2006, 124:471-484.
48. Yao J.C., Phan A.T., Chang D.Z., Wolff R.A., Hess K., Gupta S., Jacobs C., Mares J.E., Landgraf A.N., Rashid A., Meric-Bernstam F. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J. Clin. Oncol. 2008, 26:4311-4318.
49. Yao J.C., Shah M.H., Ito T., Bohas C.L., Wolim E.M., Van Cutsem E., Hobday T.J., Okusaka T., Capdevila J., de Vries E.G., Tomassetti P., Pavel M.E., Hoosen S., Haas T., Lincy J., Lebwohl D., Öberg K. RAD001 in Advanced Neuroendocrine tumors, third trial (RADIANT-3) study group. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 2011, 10:514-523.
50. Yu K., Toral-Barza L., Discafani C., Zhang W.G., Skotnicki J., Frost P., Gibbons J.J. MTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr. Relat. Cancer 2001, 8:249-258.
51. Zhang D., Bar-Eli M., Meloche S., Brodt P. Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J. Biol. Chem. 2004, 279:19683-19690.
52. Zhang H., Bajraszewski N., Wu E., Wang H., Mosenman A.P., Dabora S.L., Griffin J.D., Kwiatkowski D.J. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J. Clin. Invest. 2007, 117:730-738.
53. Zitzmann K., von Rüden J., Brand S., Göke B., Lichtl J., Spöttl G., Auernhammer C.J. Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. Cancer Lett. 2010, 295:100-109.
54. Zutzmann K., De Toni E.N., Brand S., Göke B., Meinecke J., Spöttl G., Meter H.H., Auernhammer C.J. The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology 2007, 85:54-60.