mTORC2 signaling drives the development and progression of pancreatic cancer

Cancer Research

Volumn 76, Issue 23, 2016, Pages 6911-6923

  Driscoll, David R ^a   Karim, Saadia A ^b   Sano, Makoto ^c   Gay, David M ^b   Jacob, Wright ^d   Yu, Jun ^a   Mizukami, Yusuke ^e   Gopinathan, Aarthi ^f   Jodrell, Duncan I ^f   Evans, T R Jeffry ^b,d   Bardeesy, Nabeel ^e   Hall, Michael N ^g   Quattrochi, Brian J ^a   Klimstra, David S ^h   Barry, Simon T ⁱ   Sansom, Owen J ^b,d   Lewis, Brian C ^a   Morton, Jennifer P ^b,d  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^b BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

^c NIHON UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^d UNIVERSITY OF GLASGOW   (United Kingdom)

^e MASSACHUSETTS GENERAL HOSPITAL   (United States)

^f CANCER RESEARCH UK CAMBRIDGE RESEARCH INSTITUTE   (United Kingdom)

^g UNIVERSITY OF BASEL   (Switzerland)

^h MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

ⁱ ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; ONCOPROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; RICTOR PROTEIN; UNCLASSIFIED DRUG; MTOR PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER GROWTH; CANCER STAGING; CANCER SURVIVAL; CARCINOGENESIS; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME INHIBITION; GENE INACTIVATION; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2 GENE; MOUSE; NONHUMAN; ONCOGENE K RAS; PANCREAS CANCER; PRIORITY JOURNAL; PROTEIN TARGETING; SIGNAL TRANSDUCTION; ADENOCARCINOMA; ANIMAL; DISEASE COURSE; GENETICS; HUMAN; PANCREAS CARCINOMA; PATHOLOGY; TUMOR CELL LINE;

ADENOCARCINOMA; ANIMALS; CARCINOMA, PANCREATIC DUCTAL; CELL LINE, TUMOR; DISEASE PROGRESSION; HUMANS; MICE; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 85003029923     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-16-0810     Document Type: Article

References (55)

1. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med 2014;371:2140-1.
2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
4. Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 2015;12:319-34.
5. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405.
6. Neesse A, Algul H, Tuveson DA, Gress TM. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 2015;64:1476-84.
7. Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem 2011;3:1787-808.
8. Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006;6:184-92.
9. Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 2013;23:406-20.
10. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 2013;10:143-53.
11. Huang K, Fingar DC. Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol 2014;36:79-90.
12. Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem 2008;283:35375-82.
13. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-74.
14. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375-85.
15. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006;11:859-71.
16. Kennedy AL, Morton JP, Manoharan I, Nelson DM, Jamieson NB, Pawlikowski JS, et al. Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis. Mol Cell 2011;42:36-49.
17. Cheng H, Zou Y, Ross JS, Wang K, Liu X, Halmos B, et al. RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov 2015;5:1262-70.
18. Laugier F, Finet-Benyair A, Andre J, Rachakonda PS, Kumar R, Bensussan A, et al. RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma. Oncotarget 2015;6:28120-31.
19. Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009;15:148-59.
20. Xu K, Liu P, Wei W. mTOR signaling in tumorigenesis. Biochim Biophys Acta 2014;1846:638-54.
21. Nelson V, Altman JK, Platanias LC. Next generation of mammalian target of rapamycin inhibitors for the treatment of cancer. Expert Opin Investig Drugs 2013;22:715-22.
22. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2009;2:pe24.
23. Morran DC, Wu J, Jamieson NB, Mrowinska A, Kalna G, Karim SA, et al. Targeting mTOR dependency in pancreatic cancer. Gut 2014;63:1481-9.
24. Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet 2002;32:128-34.
25. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 2006;11:583-9.
26. Bentzinger CF, Romanino K, Cloetta D, Lin S, Mascarenhas JB, Oliveri F, et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 2008;8:411-24.
27. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7:469-83.
28. Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology 2013;144:1180-93.
29. Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011;71:5020-9.
30. Schreiber FS, Deramaudt TB, Brunner TB, Boretti MI, Gooch KJ, Stoffers DA, et al. Successful growth and characterization of mouse pancreatic ductal cells: functional properties of the Ki-RAS(G12V) oncogene. Gastroenterology 2004;127:250-60.
31. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437-50.
32. Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003;17:3112-26.
33. Zheng X, Wang Y, Liu B, Liu C, Liu D, Zhu J, et al. Bmi-1-shRNA inhibits the proliferation of lung adenocarcinoma cells by blocking the G1/S phase through decreasing cyclin D1 and increasing p21/p27 levels. Nucleic Acid Ther 2014;24:210-6.
34. Bednar F, Schofield HK, Collins MA, Yan W, Zhang Y, Shyam N, et al. Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. Carcinogenesis 2015;36:730-8.
35. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19:456-69.
36. Basu B, Dean E, Puglisi M, Greystoke A, Ong M, Burke W, et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual mTORC 1/2 inhibitor AZD2014. Clin Cancer Res 2015;21:3412-9.
37. Guo Z, Zhou Y, Evers BM, Wang Q. Rictor regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells. Biochem Biophys Res Commun 2012;418:426-32.
38. Palm W, Park Y, Wright K, Pavlova NN, Tuveson DA, Thompson CB. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 2015;162:259-70.
39. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8.
40. Heid I, Lubeseder-Martellato C, Sipos B, Mazur PK, Lesina M, Schmid RM, et al. Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology 2011;141:719-30, 30 e1-7.
41. Wu CY, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV, Bien H, et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 2014;147:1405-16e7.
42. Yuzugullu H, Baitsch L, Von T, Steiner A, Tong H, Ni J, et al. A PI3K p110beta-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. Nat Commun 2015;6:8501.
43. Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, et al. Inhibition of PI3Kbeta signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel. Mol Cancer Ther 2015;14:48-58.
44. Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 2012;122:639-53.
45. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012;149:656-70.
46. Damsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, et al. mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell 2015;27:41-56.
47. Herzog A, Bian Y, Vander Broek R, Hall B, Coupar J, Cheng H, et al. PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer. Clin Cancer Res 2013;19:3808-19.
48. Ai D, Chen C, Han S, Ganda A, Murphy AJ, Haeusler R, et al. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Invest 2012;122:1262-70.
49. Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, et al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci U S A 2015;112:2473-8.
50. Liu P, Gan W, Chin YR, Ogura K, Guo J, Zhang J, et al. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov 2015;5:1194-209.
51. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296-302.
52. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009;16:21-32.
53. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6:1122-8.
54. Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, et al. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 2014;511:483-7.
55. Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 2012;149:780-94.