Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine

Gastroenterology

Volumn 150, Issue 1, 2016, Pages 48-63

  Knudsen, Erik S ^a,b   O'Reilly, Eileen M ^c   Brody, Jonathan R ^d   Witkiewicz, Agnieszka K ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS AT DALLAS   (United States)

^c MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^d THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Kras; Myc; Notch; Smad4

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; BINIMETINIB; CAPECITABINE; CYCLIN DEPENDENT KINASE 6; CYCLIN DEPENDENT KINASE INHIBITOR 2A; FLUOROURACIL; FOLINIC ACID; GEMCITABINE; K RAS PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; MONOCLONAL ANTIBODY; NOTCH RECEPTOR; OXALIPLATIN; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B INHIBITOR; SELUMETINIB; TAREXTUMAB; TRAMETINIB;

ARTICLE; CHROMATIN ASSEMBLY AND DISASSEMBLY; CHROMOSOMAL INSTABILITY; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); DNA DAMAGE; DNA REPAIR; DRUG TARGETING; GENE MUTATION; GENE TARGETING; GENETIC ANALYSIS; GENETIC VARIABILITY; HUMAN; MICROSATELLITE INSTABILITY; MOLECULARLY TARGETED THERAPY; NEXT GENERATION SEQUENCING; NONHUMAN; ONCOGENE; PANCREAS ADENOCARCINOMA; PANCREAS CANCER; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SYSTEMIC THERAPY; WNT SIGNALING PATHWAY; ADENOCARCINOMA; CANCER STAGING; CARCINOMA, PANCREATIC DUCTAL; FEMALE; GENE THERAPY; GENETIC PREDISPOSITION; GENETICS; MALE; MORTALITY; MULTIMODALITY CANCER THERAPY; PANCREAS RESECTION; PANCREATIC NEOPLASMS; PATHOLOGY; PROCEDURES; PROGNOSIS; RISK ASSESSMENT; SURVIVAL ANALYSIS; TUMOR INVASION;

ADENOCARCINOMA; CARCINOMA, PANCREATIC DUCTAL; COMBINED MODALITY THERAPY; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENETIC THERAPY; HUMANS; MALE; NEOPLASM INVASIVENESS; NEOPLASM STAGING; PANCREATECTOMY; PANCREATIC NEOPLASMS; PRECISION MEDICINE; PROGNOSIS; RISK ASSESSMENT; SURVIVAL ANALYSIS;

EID: 84952682738     PISSN: 00165085     EISSN: 15280012     Source Type: Journal    
DOI: 10.1053/j.gastro.2015.08.056     Document Type: Review

References (140)

1. A. Vincent, J. Herman, R. Schulick, and et al. Pancreatic cancer Lancet 378 2011 607 620
2. C.J. Yeo, J.L. Cameron, T.A. Sohn, and et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes Ann Surg 226 1997 248 257 discussion 257-260
3. D.E. Kardon, L.D. Thompson, R.M. Przygodzki, and et al. Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases Mod Pathol 14 2001 443 451
4. R.E. Wilentz, J. Albores-Saavedra, M. Zahurak, and et al. Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas Am J Surg Pathol 23 1999 1320 1327
5. L. Rahib, B.D. Smith, R. Aizenberg, and et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States Cancer Res 74 2014 2913 2921
6. C.J. Yeo, J.L. Cameron, K.D. Lillemoe, and et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients Ann Surg 221 1995 721 731 discussion 731-733
7. T. Conroy, F. Desseigne, M. Ychou, and et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 364 2011 1817 1825
8. M.W. Saif Advancements in the management of pancreatic cancer: 2013 JOP 14 2013 112 118
9. D.D. Von Hoff, T. Ervin, F.P. Arena, and et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 369 2013 1691 1703
10. M.J. Moore, D. Goldstein, J. Hamm, and et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 25 2007 1960 1966
11. A.S. Paulson, H.S. Tran Cao, M.A. Tempero, and et al. Therapeutic advances in pancreatic cancer Gastroenterology 144 2013 1316 1326
12. A. Maitra, and R.H. Hruban Pancreatic cancer Annu Rev Pathol 3 2008 157 188
13. K. Forrester, C. Almoguera, K. Han, and et al. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis Nature 327 1987 298 303
14. K.H. Herzig, M. Schaffer, S. Rosewicz, and et al. [Detection of mutated ras-oncogene in pancreatic cancers: improved diagnostic possibilities using molecular biology techniques?] Z Gastroenterol 30 1992 436 439
15. N.R. Lemoine Molecular advances in pancreatic cancer Digestion 58 1997 550 556
16. H. Ying, A.C. Kimmelman, C.A. Lyssiotis, and et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism Cell 149 2012 656 670
17. L. Johnson, K. Mercer, D. Greenbaum, and et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice Nature 410 2001 1111 1116
18. N. Bardeesy, and R.A. DePinho Pancreatic cancer biology and genetics Nat Rev Cancer 2 2002 897 909
19. D.A. Tuveson, and S.R. Hingorani Ductal pancreatic cancer in humans and mice Cold Spring Harb Symp Quant Biol 70 2005 65 72
20. A.J. Aguirre, N. Bardeesy, M. Sinha, and et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma Genes Dev 17 2003 3112 3126
21. A. Scarpa, P. Capelli, K. Mukai, and et al. Pancreatic adenocarcinomas frequently show p53 gene mutations Am J Pathol 142 1993 1534 1543
22. H. Kalthoff, W. Schmiegel, C. Roeder, and et al. p53 and K-RAS alterations in pancreatic epithelial cell lesions Oncogene 8 1993 289 298
23. S.R. Hingorani, L. Wang, A.S. Multani, and et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice Cancer Cell 7 2005 469 483
24. M. Schutte, R.H. Hruban, J. Geradts, and et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas Cancer Res 57 1997 3126 3130
25. D.K. Bartsch, M. Sina-Frey, S. Lang, and et al. CDKN2A germline mutations in familial pancreatic cancer Ann Surg 236 2002 730 737
26. S.A. Hahn, M. Schutte, A.T. Hoque, and et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science 271 1996 350 353
27. F. Liu, A. Hata, J.C. Baker, and et al. A human Mad protein acting as a BMP-regulated transcriptional activator Nature 381 1996 620 623
28. A. Blackford, O.K. Serrano, C.L. Wolfgang, and et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer Clin Cancer Res 15 2009 4674 4679
29. C.A. Iacobuzio-Donahue, B. Fu, S. Yachida, and et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer J Clin Oncol 27 2009 1806 1813
30. R.H. Hruban, M. Goggins, J. Parsons, and et al. Progression model for pancreatic cancer Clin Cancer Res 6 2000 2969 2972
31. M. Imielinski, A.H. Berger, P.S. Hammerman, and et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing Cell 150 2012 1107 1120
32. Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours Nature 490 2012 61 70
33. A. Neesse, P. Michl, K.K. Frese, and et al. Stromal biology and therapy in pancreatic cancer Gut 60 2010 861 868
34. S. Jones, X. Zhang, D.W. Parsons, and et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses Science 321 2008 1801 1806
35. A.V. Biankin, N. Waddell, K.S. Kassahn, and et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes Nature 491 2012 399 405
36. N. Waddell, M. Pajic, A.M. Patch, and et al. Whole genomes redefine the mutational landscape of pancreatic cancer Nature 518 2015 495 501
37. Cancer Genome Atlas Research Network Comprehensive genomic characterization of squamous cell lung cancers Nature 489 2012 519 525
38. S.J. Murphy, S.N. Hart, J.F. Lima, and et al. Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor Gastroenterology 145 2013 1098 1109 e1
39. A.K. Witkiewicz, E.A. McMillan, U. Balaji, and et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets Nat Commun 6 2015 6744
40. Iacobuzio-Donahue CA, Velculescu VE, Wolfgang CL, et al. Genetic basis of pancreas cancer development and progression: insights from whole-exome and whole-genome sequencing. Clin Cancer Res;18:4257-4265.
41. S. Yachida, and C.A. Iacobuzio-Donahue Evolution and dynamics of pancreatic cancer progression Oncogene 32 2013 5253 5260
42. S. Yachida, S. Jones, I. Bozic, and et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer Nature 467 2010 1114 1117
43. M.S. Lawrence, P. Stojanov, P. Polak, and et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes Nature 499 2013 214 218
44. M.S. Lawrence, P. Stojanov, C.H. Mermel, and et al. Discovery and saturation analysis of cancer genes across 21 tumour types Nature 505 2014 495 501
45. T. Furukawa, Y. Kuboki, E. Tanji, and et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas Sci Rep 1 2011 161
46. J. Wu, H. Matthaei, A. Maitra, and et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development Sci Transl Med 3 2011 92ra66
47. E. Amato, M.D. Molin, A. Mafficini, and et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas J Pathol 233 2014 217 227
48. E.S. Calhoun, T. Hucl, E. Gallmeier, and et al. Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays Cancer Res 66 2006 7920 7928
49. C.H. Mermel, S.E. Schumacher, B. Hill, and et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers Genome Biol 12 2011 R41
50. J.N. Anastas, and R.T. Moon WNT signalling pathways as therapeutic targets in cancer Nat Rev Cancer 13 2013 11 26
51. U. Asghar, A.K. Witkiewicz, N.C. Turner, and et al. The history and future of targeting cyclin-dependent kinases in cancer therapy Nat Rev Drug Discov 14 2015 130 146
52. S. Jones, R.H. Hruban, M. Kamiyama, and et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene Science 324 2009 217
53. A.P. Klein Genetic susceptibility to pancreatic cancer Mol Carcinog 51 2012 14 24
54. D.B. Zhen, K.G. Rabe, S. Gallinger, and et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study Genet Med 17 2015 569 577
55. F. Kastrinos, B. Mukherjee, N. Tayob, and et al. Risk of pancreatic cancer in families with Lynch syndrome JAMA 302 2009 1790 1795
56. M. Goggins, G.J. Offerhaus, W. Hilgers, and et al. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+ Am J Pathol 152 1998 1501 1507
57. R.E. Wilentz, M. Goggins, M. Redston, and et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity Am J Pathol 156 2000 1641 1651
58. L. Laghi, S. Beghelli, A. Spinelli, and et al. Irrelevance of microsatellite instability in the epidemiology of sporadic pancreatic ductal adenocarcinoma PLoS One 7 2012 e46002
59. L.B. Alexandrov, S. Nik-Zainal, D.C. Wedge, and et al. Signatures of mutational processes in human cancer Nature 500 2013 415 421
60. C.J. Lord, and A. Ashworth Targeted therapy for cancer using PARP inhibitors Curr Opin Pharmacol 8 2008 363 369
61. L.A. Chantrill, A.M. Nagrial, C. Watson, and et al. Precision medicine for advanced pancreas cancer: the Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial Clin Cancer Res 21 2015 2029 2037
62. F. McCormick KRAS as a therapeutic target Clin Cancer Res 21 2015 1797 1801
63. H. Thompson US National Cancer Institute's new Ras project targets an old foe Nat Med 19 2013 949 950
64. H. Hamidi, M. Lu, K. Chau, and et al. KRAS mutational subtype and copy number predict in vitro response of human pancreatic cancer cell lines to MEK inhibition Br J Cancer 111 2014 1788 1801
65. E. Zorde Khvalevsky, R. Gabai, I.H. Rachmut, and et al. Mutant KRAS is a druggable target for pancreatic cancer Proc Natl Acad Sci U S A 110 2013 20723 20728
66. A. Kapoor, W. Yao, H. Ying, and et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer Cell 158 2014 185 197
67. A. Viale, P. Pettazzoni, C.A. Lyssiotis, and et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function Nature 514 2014 628 632
68. B. Alagesan, G. Contino, A.R. Guimaraes, and et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer Clin Cancer Res 21 2015 396 404
69. E.A. Collisson, C.L. Trejo, J.M. Silva, and et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma Cancer Discov 2 2012 685 693
70. G. Bodoky, C. Timcheva, D.R. Spigel, and et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy Invest New Drugs 30 2012 1216 1223
71. J. Rinehart, A.A. Adjei, P.M. Lorusso, and et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer J Clin Oncol 22 2004 4456 4462
72. J.R. Infante, B.G. Somer, J.O. Park, and et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas Eur J Cancer 50 2014 2072 2081
73. M. Dal Molin, M. Zhang, R.F. de Wilde, and et al. Very long-term survival following resection for pancreatic cancer is not explained by commonly mutated genes: results of whole-exome sequencing analysis Clin Cancer Res 21 2015 1944 1950
74. L.A. Chantrill, A.M. Nagrial, C. Watson, and et al. Precision medicine for advanced pancreas cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial Clin Cancer Res 21 2015 2029 2037
75. M.S. van der Heijden, J.R. Brody, D.A. Dezentje, and et al. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor Clin Cancer Res 11 2005 7508 7515
76. M.S. van der Heijden, J.R. Brody, E. Gallmeier, and et al. Functional defects in the fanconi anemia pathway in pancreatic cancer cells Am J Pathol 165 2004 651 657
77. M.S. van der Heijden, C.J. Yeo, R.H. Hruban, and et al. Fanconi anemia gene mutations in young-onset pancreatic cancer Cancer Res 63 2003 2585 2588
78. E. Gallmeier, E.S. Calhoun, C. Rago, and et al. Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options Gastroenterology 130 2006 2145 2154
79. M.A. Lowery, D.P. Kelsen, Z.K. Stadler, and et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions Oncologist 16 2011 1397 1402
80. M. Lowery, M.A. Shah, E. Smyth, and et al. A 67-year-old woman with BRCA 1 mutation associated with pancreatic adenocarcinoma J Gastrointest Cancer 42 2011 160 164
81. T. Golan, Z.S. Kanji, R. Epelbaum, and et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers Br J Cancer 111 2014 1132 1138
82. A. Ashworth Drug resistance caused by reversion mutation Cancer Res 68 2008 10021 10023
83. A. Ashworth A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair J Clin Oncol 26 2008 3785 3790
84. T. Hucl, C. Rago, E. Gallmeier, and et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2 Cancer Res 68 2008 5023 5030
85. E.M. O'Reilly, M.A. Lowery, M.F. Segal, and et al. Phase IB trial of cisplatin (C), gemcitabine (G), and veliparib (V) in patients with known or potential BRCA or PALB2-mutated pancreas adenocarcinoma (PC) ASCO Meeting Abstracts 32 2014 4023
86. M.J. Pishvaian, H. Wang, T. Zhuang, and et al. A phase I/II study of ABT-888 in combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with metastatic pancreatic cancer (MPC) J Clin Oncol Suppl 4; abstr 147 2013 31
87. J. Bendell, E.M. O'Reilly, M.R. Middleton, and et al. Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer Ann Oncol 26 2015 804 811
88. B. Kaufman, R. Shapira-Frommer, R.K. Schmutzler, and et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation J Clin Oncol 33 2015 244 250
89. M.A. Lowery, D.P. Kelsen, S.C. Smith, and et al. Phase II trial of veliparib (V) in patients (pts) with previously treated BRCA or PALB2-mutated (mut) pancreas adenocarcinoma (PC) ASCO Meeting Abstracts 33 2015 358
90. K. Do, and A.P. Chen Molecular pathways: targeting PARP in cancer treatment Clin Cancer Res 19 2013 977 984
91. M. Aarts, R. Sharpe, I. Garcia-Murillas, and et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1 Cancer Discov 2 2012 524 539
92. K.A. Bridges, H. Hirai, C.A. Buser, and et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells Clin Cancer Res 17 2011 5638 5648
93. N.V. Rajeshkumar, E. De Oliveira, N. Ottenhof, and et al. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts Clin Cancer Res 17 2011 2799 2806
94. C. Caldas, S.A. Hahn, L.T. da Costa, and et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma Nat Genet 8 1994 27 32
95. N. Fukushima, N. Sato, T. Ueki, and et al. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma Am J Pathol 160 2002 1573 1581
96. A.K. Witkiewicz, K.E. Knudsen, A.P. Dicker, and et al. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments Cell Cycle 10 2011 2497 2503
97. M. Serrano, E. Gomez-Lahoz, R.A. DePinho, and et al. Inhibition of ras-induced proliferation and cellular transformation by p16INK4 Science 267 1995 249 252
98. M. Serrano, A.W. Lin, M.E. McCurrach, and et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a Cell 88 1997 593 602
99. F. Liu, and M. Korc Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells Mol Cancer Ther 11 2012 2138 2148
100. A.M. Heilmann, R.M. Perera, V. Ecker, and et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers Cancer Res 74 2014 3947 3958
101. J. Franco, A.K. Witkiewicz, and E.S. Knudsen CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer Oncotarget 5 2014 6512 6525
102. R.S. Finn, J.P. Crown, I. Lang, and et al. Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) Cancer Res 74 Suppl 2014 CT101
103. E.R. Fearon Molecular genetics of colorectal cancer Annu Rev Pathol 6 2011 479 507
104. M. Pasca di Magliano, A.V. Biankin, P.W. Heiser, and et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma PLoS One 2 2007 e1155
105. P.W. Heiser, D.A. Cano, L. Landsman, and et al. Stabilization of beta-catenin induces pancreas tumor formation Gastroenterology 135 2008 1288 1300
106. X. Jiang, H.X. Hao, J.D. Growney, and et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma Proc Natl Acad Sci U S A 110 2013 12649 12654
107. P. Ranganathan, K.L. Weaver, and A.J. Capobianco Notch signalling in solid tumours: a little bit of everything but not all the time Nat Rev Cancer 11 2011 338 351
108. E.R. Andersson, and U. Lendahl Therapeutic modulation of Notch signalling - are we there yet? Nat Rev Drug Discov 13 2014 357 378
109. H. Doucas, C.D. Mann, C.D. Sutton, and et al. Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt J Surg Oncol 97 2008 63 68
110. C.D. Mann, C. Bastianpillai, C.P. Neal, and et al. Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma PLoS One 7 2012 e51119
111. M.M. Thomas, Y. Zhang, E. Mathew, and et al. Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis BMC Cancer 14 2014 862
112. V. Palagani, P. Bozko, M. El Khatib, and et al. Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression Carcinogenesis 35 2014 859 866
113. M. Mizuma, Z.A. Rasheed, S. Yabuuchi, and et al. The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models Mol Cancer Ther 11 2012 1999 2009
114. S. Yabuuchi, S.G. Pai, N.R. Campbell, and et al. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer Cancer Lett 335 2013 41 51
115. N. Cook, K.K. Frese, T.E. Bapiro, and et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma J Exp Med 209 2012 437 444
116. W.C. Yen, M.M. Fischer, F. Axelrod, and et al. Targeting notch signaling with a notch2/notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency Clin Cancer Res 21 2015 2084 2095
117. E.M. O'Reilly, L.S. Smith, J.C. Bendell, and et al. Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC) ASCO Meeting Abstracts 33 2015 278
118. C. Kadoch, D.C. Hargreaves, C. Hodges, and et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy Nat Genet 45 2013 592 601
119. B.G. Wilson, and C.W. Roberts SWI/SNF nucleosome remodellers and cancer Nat Rev Cancer 11 2011 481 492
120. K.C. Helming, X. Wang, B.G. Wilson, and et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers Nat Med 20 2014 251 254
121. B.G. Bitler, K.M. Aird, A. Garipov, and et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers Nat Med 21 2015 231 238
122. C.H. Huang, A. Lujambio, J. Zuber, and et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma Genes Dev 28 2014 1800 1814
123. J.E. Delmore, G.C. Issa, M.E. Lemieux, and et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc Cell 146 2011 904 917
124. H. Hirai, T. Arai, M. Okada, and et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil Cancer Biol Ther 9 2010 514 522
125. A. Prahallad, C. Sun, S. Huang, and et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR Nature 483 2012 100 103
126. S.F. Boj, C.I. Hwang, L.A. Baker, and et al. Organoid models of human and mouse ductal pancreatic cancer Cell 160 2015 324 338
127. X. Liu, V. Ory, S. Chapman, and et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells Am J Pathol 180 2012 599 607
128. H. Yuan, S. Myers, J. Wang, and et al. Use of reprogrammed cells to identify therapy for respiratory papillomatosis N Engl J Med 367 2012 1220 1227
129. J.C. Francis, L. Melchor, J. Campbell, and et al. Whole exome DNA sequence analysis of Brca2 and Trp53 deficient mouse mammary gland tumours J Pathol 236 2015 186 200
130. P.M. Westcott, K.D. Halliwill, M.D. To, and et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer Nature 517 2015 489 492
131. J.R. Brody, E. Gallmeier, K. Yoshimura, and et al. A proposed clinical test for monitoring fluoropyrimidine therapy: detection and stability of thymidylate synthase ternary complexes Cancer Biol Ther 5 2006 923 927
132. K. Patel, C.A. Iacobuzio-Donahue, P.E. Gormley, and et al. Are we systematically under-dosing patients with fluorouracil? J Clin Oncol 33 2015 e36 e37
133. A.H. Ko, J. Hwang, A.P. Venook, and et al. Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer Br J Cancer 93 2005 195 199
134. A. Chan, I. Prassas, A. Dimitromanolakis, and et al. Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer Clin Cancer Res 20 2014 5787 5795
135. S.L. Topalian, M. Sznol, D.F. McDermott, and et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab J Clin Oncol 32 2014 1020 1030
136. S.A. Rosenberg, and N.P. Restifo Adoptive cell transfer as personalized immunotherapy for human cancer Science 348 2015 62 68
137. K.C. Soares, A.A. Rucki, A.A. Wu, and et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors J Immunother 38 2015 1 11
138. D.T. Le, J.N. Uram, H. Wang, and et al. PD-1 blockade in tumors with mismatch-repair deficiency N Engl J Med 372 2015 2509 2520
139. P.P. Provenzano, C. Cuevas, A.E. Chang, and et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma Cancer Cell 21 2012 418 429
140. B.A. Conley, and J.H. Doroshow Molecular analysis for therapy choice: NCI MATCH Semin Oncol 41 2014 297 299